Open Access

NLRP3 inflammasome in health and disease (Review)

  • Authors:
    • Haoran Wang
    • Li Ma
    • Weiran Su
    • Yangruoyu Liu
    • Ning Xie
    • Jun Liu
  • View Affiliations

  • Published online on: January 20, 2025     https://doi.org/10.3892/ijmm.2025.5489
  • Article Number: 48
  • Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Activation of inflammasomes is the activation of inflammation‑related caspase mediated by the assembly signal of multi‑protein complex and the maturity of inflammatory factors, such as IL‑1β and IL‑18. Among them, the Nod‑like receptor family pyrin domain containing 3 (NLRP3) inflammasome is the most thoroughly studied type of inflammatory corpuscle at present, which is involved in the occurrence and development of numerous human diseases. Therefore, targeting the NLRP3 inflammasome has become the focus of drug development for related diseases. In this paper, the research progress of the NLRP3 inflammasome in recent years is summarized, including the activation and regulation of NLRP3 and its association with diseases. A deep understanding of the regulatory mechanism of NLRP3 will be helpful to the discovery of new drug targets and the development of therapeutic drugs.

Introduction

Nod-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is mainly expressed in the cytoplasm of natural immune cells such as macrophages, and it is the most deeply studied inflammatory corpuscle complex at present. When NLRP3 is specifically stimulated, it recruits the connexin apoptosis-associated spot-like protein (ASC) and the effector protein pro-caspase-1 to start the assembly and activation of the inflammatory complex. The activated inflammatory body of NLRP3 mediates the self-shearing of pro-caspase-1 and produces caspase-1 with enzyme activity. On the one hand, caspase-1 can cleave pro-IL-1β and pro-IL-18, and promote the maturation and secretion of IL-1β and IL-18; on the other hand, caspase-1 can cleave gasdermin D (GSDMD) and release its N-terminus. The N-terminus of GSDMD forms a hole in the cell membrane and induces inflammatory cell death, that is, pyroptosis (1). The NLRP3 inflammasome is activated not only by a variety of ligands from pathogens and environmental sources, such as microbial cell wall components, nucleic acids, Alum, silica, aluminium hydroxide, nanoparticles, crystalline silicon dioxide, carbon nanotubes and chitosan, but also by endogenous danger signals, such as lipopolysaccharides (LPS), adenosine triphosphate (ATP), uric acid crystal, serum amyloid, prion protein, biglycan, hyaluronan, islet amyloid polypeptide, hydroxyapatite, haeme, oxidized mitochondrial DNA and membrane attack complex (2-4). The activation of the NLRP3 inflammasome plays an important role in pathogen clearance and adaptive immune response induction. However, the abnormal activation of the NLRP3 inflammasome leads to excessive inflammatory response, which in turn promotes the occurrence and development of numerous inflammatory diseases. Therefore, it is involved in the occurrence and development of many major human diseases, including Alzheimer's disease (AD), autoimmune diseases and arteriosclerosis (5,6). Therefore, the NLRP3 inflammasome is an important target to treat these major human diseases. It is of great significance to clarify the activation and regulation mechanism of NLRP3 inflammatory corpuscles and develop therapeutic drugs for the NLRP3 inflammasome. In this paper, the activation mechanism of the NLRP3 inflammasome and a series of related diseases are reviewed in order to provide a theoretical basis and new ideas for the prevention and treatment of inflammation-related diseases.

Structural characteristics of the NLRP3 inflammasome

The NLRP3 inflammasome is a high-molecular-weight intracellular multi-protein complex, which consists of NLRP3, apoptosis-associated speck-like protein containing card (ASC) and pro-caspase-1. NLRP3 is a member of the NLRs protein family, including three domains: An N-terminal pyrin domain (PYD), a central NBD-containing ATPase domain called NACHT and a C-terminal Leucine-rich repeat (LRR). ASC is a scaffold protein connecting NLRP3 and pro-caspase-1, and pro-caspase-1 is an inactive precursor of caspase-1. Caspase-1 produced by its activation is the effector protein of the NLRP3 inflammatory body. NLRP3 recruits ASC under the action of various agonists to form the NLRP3 inflammasome by combining ASC with pro-caspase-1 (7-9).

Activation mechanism of NLRP3 inflammasome

The NLRP3 inflammasome is closely related to numerous major human diseases, so it is important to clarify its activation mechanism. Since the concept of the NLRP3 inflammasome was first put forward in 2002, Kelley et al (10) discovered the classical, non-classical and alternative pathways of NLRP3 inflammasome activation. In this chapter, the activation mechanisms of these three pathways will be briefly introduced.

Classical activation pathway of the NLRP3 inflammasome

The classical activation pathway of the NLRP3 inflammasome includes priming and activation. The priming process means that cells are exposed to various stimuli, such as Toll-like receptors (TLRs) and NLD-like receptors, and then the transcription factor NF-ĸB is activated, thus upregulating the expression of pro-IL-1β and NLRP3 (10,11). The activation process means that cells treated by the priming process are activated by pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), and proteins such as NLRP3, ASC and pro-caspase-1 are assembled into inflammatory corpuscles, thus inducing cell apoptosis and IL-1β and IL-18 to activate the NLRP3 inflammasome. It is generally thought that there are three kinds of molecular and cellular signaling events induced by NLRP3 agonists (11,12) (Fig. 1).

Ion flow

Intracellular K+ outflow is the first signaling pathway to activate the NLRP3 inflammasome (13). Previous studies have confirmed that low-K solution promotes the activation of the NLRP3 inflammasome, while high-K solution can inhibit the activation of the NLRP3 inflammasome by blocking K+ outflow, and numerous NLRP3 activators, such as bacteriocin, ATP, granular molecules and crystalline substances, directly cause intracellular to extracellular flow of K+, thus activating the NLRP3 inflammasome (13). Further mechanistic research confirmed that the purinergic receptor (P2X7) on the cell membrane and the K family member 6/TWIK2 of the K+ double-pore channel are jointly responsible for regulating the intracellular K+ outflow, which leads to the activation of the NLRP3 inflammasome (14). However, previous research shows that certain small molecules activate the NLRP3 inflammasome without relying on potassium ion outflow, such as imiquimod, CL097 and peptidoglycan-induced activation of the NLRP3 inflammasome, and accordingly, K+ outflow is a sufficient condition for activation of the NLRP3 inflammasome, but it is not a necessary condition (15,16). It is worth noting that the outflow of K+ is closely related to the potassium-acid balance in the body, and acidosis will lead to the release of K+ from the inside to the outside of the cell, thus increasing the concentration of K+ in the blood. Rajamäki et al (17) confirmed that extracellular acidosis activates NLRP3 inflammatory corpuscles in macrophages, which leads to enhanced caspase-1 processing and IL-1β secretion. Acute exposure to an acidic environment did not induce the activation of NLRP3 inflammatory bodies, which indicates that an acidic pH is not a direct activation factor (18).

The role of Ca2+ flow in the activation of inflammatory corpuscles in NLRP3 is still controversial. As a second messenger, Ca2+ has an important role in cell signal transduction and the disorder of Ca2+ flow has disastrous consequences for cells. Ca2+ receptor activator C promotes the expression of inositol 1,4,5-triphosphate and induces the release of Ca2+ from the endoplasmic reticulum, thus activating the NLRP3 inflammasome (19). Early studies have confirmed that Ca2+ chelating agent BAPTA-AM inhibited the activation of the NLRP3 inflammasome and the secretion of IL-1β (20-22). Furthermore, Katsnelson et al (23) also found that numerous NLRP3 agonists cause changes of intracellular Ca2+. However, certain studies have also found that the Ca2+ chelating agent BAPTA-AM is independent of Ca2+ flow, indicating that Ca2+ flow may not be necessary for the activation of NLRP3 inflammasome, but it may play a regulatory role in this process.

One study indicated that a decrease in the CI concentration enhanced the activation of the NLRP3 inflammasome and the secretion of IL-1β (24). On the contrary, an increase in the concentration of extracellular CI inhibited the secretion of IL-1β. Certain studies further confirmed that CIchannel inhibitors inhibit the activation of NLRP3 inflammasome (24,25). Furthermore, chloride intracellular channels (CLIC), the CI channel, is involved in the activation of the NLRP3 inflammasome. As the next event of mitochondrial reactive oxygen species (ROS), the outflow of CI mediated by CLICs induces the activation of NLRP3 inflammasome by promoting the interaction between NIMA-related kinase 7 (NEK7) and NLRP3 (24). However, it remains elusive how the outflow of CI enhances the interaction between NEK7 and NLRP3. In addition, another study found that WNK lysine-deficient protein kinase 1 regulates Cl/cation synergistic transporter and reduces the outflow of CI to inhibit the activation of NLRP3 inflammasome, but Cl/cation co-transporter not only regulates the outflow of CI, but also affects the outflow of K+ (26). Furthermore, the intracellular Cl efflux induced by low-Cl solution does not activate the NLRP3 inflammasome, and accordingly, Cl efflux may trigger the activation of NLRP3 inflammasome by cooperating with other signaling pathways (27).

Na+ was previously reported to be involved in the activation of the NLRP3 inflammasome. The results showed that decreasing the concentration of extracellular Na+ could inhibit the activation of the NLRP3 inflammasome induced by Nigericin and bacitracin, but Na+ could not affect the activation of NLRP3 inflammasome induced by ATP and other factors, indicating that Na+ influx alone is not sufficient to activate the NLRP3 inflammasome, which may be due to the synergistic effect of Na+ influx and intracellular K+ outflow, and the activation of the NLRP3 inflammasome by Na+ influx depends on K+ (13). Therefore, Na+ influx may indirectly activate the NLRP3 inflammasome by triggering intracellular K+ outflow.

Generation of ROS

The production of ROS is an important signal for the activation of the NLRP3 inflammasome. Most NLRP3 agonists induce cells to produce ROS. Under normal physiological conditions, there is a low level of ROS in the body, which participate in the process of cell proliferation and apoptosis. However, when the body is in a pathological state, mitochondrial damage leads to an increase in ROS production, thus activating the NLRP3 inflammasome. In 2011, Zhou et al (28) discovered for the first time that the accumulation of damaged mitochondria would increase the production of ROS, which in turn would activate the NLRP3 inflammasome. Subsequently, a large number of studies confirmed that the increase of ROS induced by various factors would lead to the activation of NLRP3 inflammasome (29). In the follow-up study, Shimada et al (30) found that certain NLRP3 agonists promote the release of mitochondrial DNA into the cytoplasm in a way that depends on mitochondrial ROS, and oxidized mitochondrial DNA was indicated to be the key substance to activate NLRP3 inflammasome. However, certain scholars have found that linezolid and bacitracin promote the activation of the NLRP3 inflammasome in a way independent of mitochondrial ROS, and even certain serum β-amyloid proteins and viruses can activate NLRP3 inflammasome independent of ROS (13,29,31).

Lysosome rupture

In 2008, it was found for the first time that amyloid β protein induced lysosomes to dissolve, which in turn activated the NLRP3 inflammasome (32). Furthermore, Lima et al (33) found that a series of granular substances, such as urate crystals and asbestos, could damage lysosomes after being swallowed by cells, which led to the leakage of lysosomes into the cytoplasm, and then activated the NLRP3 inflammasome. When particulate matter (such as urate crystals) is swallowed into lysosomes, ion flow and intracellular osmotic pressure will change, bile will lead to K+ outflow and activation of NLRP3 inflammasome, and tissue protease inhibitors also inhibit particle-induced activation of the NLRP3 inflammasome (34). Cathepsin B was originally considered the key lysosomal enzyme, as its inhibitor inhibits the activation of the NLRP3 inflammasome, and particulate matter also promotes the release of cathepsin when activating the NLRP3 inflammasome (32,35). However, in a cell experiment with cathepsin B deficiency, Dostert et al (36) found the activation level of NLRP3 inflammasome to be equivalent to that of wild-type cells, which is also contrary to previous research results. Orlowski et al (37) have also found that, besides inhibiting cathepsin B, the expression of cathepsin X, L or S genes has no effect on the activation of the NLRP3 inflammasome. However, the activation of NLRP3 inflammasome by exogenous particles is accompanied by K+ outflow and Ca2+ inflow, which indicates that lysosomal cleavage may trigger an ion current in the process of activation of the NLRP3 inflammasome, thus activating the NLRP3 inflammasome, so the signal of K+ and Ca2+ slurry flow is a downstream event of lysosomal rupture (37).

Non-classical activation pathway of the NLRP3 inflammasome

In addition to the above classical pathways, more and more scholars have found that there are other activation pathways for the NLRP3 inflammasome. The molecular mechanism of the activation pathway of the non-classical NLRP3 inflammasome was studied and the researchers found that mouse caspase-11 activates the NLRP3 inflammasome by directly recognizing LPS released into the cytoplasm during infection by Gram-negative bacteria. This process is known as the non-classical activation pathway of the NLRP3 inflammasome (38,39). In further research, related researchers found that the secretion of IL-1β was significantly inhibited in mice with caspase-11 gene knockout infected with Gram-negative bacilli. Kayagaki et al (39) reasoned that this was because the cells with caspase-11 gene knockout lacked the step of caspase-11 to cut its substrate protein GSDMD. In general, only after this step is completed can the substrate protein form a cavity on the cell membrane. Then it causes K+ outflow, apoptosis and activation of the NLRP3 inflammasome (the function of human caspase-4/5 is similar to that of mouse caspase-11) (39). Gram-negative bacteria in the cytoplasm release LPS directly, thus activating caspase-4/5/11. Activated caspase-4/11 can cleave GSDMD, resulting in the formation of cell membrane pores and cell death, but caspase-4/5/11 itself does not have the function of cleaving pro-IL-1β and pro-IL-18. Cell membrane pores formed by GSDMD promote the activation of NLRP3 inflammasome by triggering K+ outflow, thus inducing the activation of caspase-1 and the mature secretion of IL-1β and IL-18 (40-42) (Fig. 2).

Alternative activation pathways of the NLRP3 inflammasome

In addition to the classical and non-classical pathways, there is an alternative activation of the NLRP3 inflammasome. It has been shown that LPS stimulation activates inflammatory bodies in monocytes through its receptor TLR4 signaling pathway. Most scholars find that LPS stimulation causes ATP to be released outside the cells, and then combine with ATP-gated K+ channel P2X7, resulting in K+ outflow, which is the key to the activation of the NLRP3 inflammasome (43). Others have confirmed that LPS stimulation activates NLRP3 inflammasome through the TLR4/TIR-domain-containing adaptor-inducing interferon-β/serine/threonine kinase-1/Fas-associated protein with death domain/caspase 8 signaling axis, promoting the activation of caspase-1 and the mature secretion of IL-1β and IL-18 (44). However, it is interesting that the alternative pathways have obvious cell and species characteristics, which has only been verified in human and pig monocytes and mouse dendritic cells (43,45) (Fig. 2).

NLRP3 inflammasome-related diseases

NLRP3 is an important aseptic inflammatory signal receptor and a key regulator of chronic inflammatory diseases. It was first discovered in 2001 and then further confirmed, researchers have found that the autosomal dominant mutation of the NLRP3 gene leads to a series of inflammatory diseases and the NLRP3 inflammasome has attracted extensive attention in related disease research fields. The NLRP3 inflammasome is subject to research on diseases in almost every system, but there is no doubt that the diseases of the respiratory system, cardiovascular system, digestive system, bone and joint system and central nervous system are the most important diseases.

NLRP3 inflammasome drives respiratory system diseases

Various pathogens in the air get in contact with pattern recognition receptors co-expressed by airway epithelial cells, alveolar macrophages or neutrophils in the lung, activating downstream signal transduction and triggering innate immune response. Studies have shown that the early immune response of the lung to harmful stimuli can be mediated by the NLRP3 inflammasome, which promotes the release of inflammatory factors, thus playing a protective role, but excessive inflammatory response will aggravate tissue damage and lead to a series of respiratory diseases. This part summarizes the research on NLRP3 inflammasome in the respiratory system (Table I).

Table I

NLRP3 inflammasome drives respiratory system diseases.

Table I

NLRP3 inflammasome drives respiratory system diseases.

DiseaseRelated mechanism(Refs.)
COPDEpithelial cells, macrophages and dendritic cells in the lung, stimulated by harmful particles or gases, activate the NLRP3 inflammasome through the NF-ĸB signaling pathway or P2X7 receptor pathway, thus promoting the release of inflammatory factors such as IL-1β and IL-18, and leading to inflammatory reaction.(46-54)
Bronchial asthmaAirway macrophages, epithelial cells and dendritic cells are stimulated by allergens to activate the NLRP3 inflammasome and then promote the release of IL-1β and IL-18 to induce inflammation.(55-70)
SilicosisSiO2 can stimulate the assembly of adaptor factors such as NLRP3 and ASC in macrophages, promote the secretion of IL-1β under the mediation of caspase-1 and participate in the occurrence of diseases.(71-73)
Bacterial infectious pneumoniaNLRP3 inflammasome mediates the lung injury induced by α-hemolysin, and α-hemolysin activates the processing and secretion of IL-1β in a way similar to pore-forming toxin, which further aggravates the progress of Staphylococcus aureus pneumonia. Streptococcus pneumoniae hemolysin can also interfere with the plasma membrane and cause K+ outflow, and then activate the NLRP3 inflammasome, trigger the secretion of IL-1β and IL-18, and aggravate the course of Streptococcus pneumoniae pneumonia.(74-77)
(78-80)

[i] NLRP3, Nod-like receptor family pyrin domain containing 3; COPD, chronic obstructive pulmonary disease; ASC, connexin apoptosis-associated spot-like protein; NF-κB, nuclear factor κB; P2X7, ATP receptor.

NLRP3 inflammasome participates in chronic obstructive pulmonary disease (COPD)

COPD is an irreversible chronic progressive lung disease characterized by continuous airflow limitation. The exact cause of COPD has so far remained elusive. Inhaling harmful particles or gases is an important cause of COPD and airway inflammation. These substances act on pulmonary epithelial cells, macrophages and dendritic cells, accelerating the synthesis and release of inflammatory factors and tissue-degrading enzymes, accelerating the development of inflammation and the destruction of lung structure. Previous studies have confirmed that inhalation of harmful substances directly activates the lung recognition receptor TLR, thus activating the downstream NF-ĸB signaling pathway, and promotes the transcription of NLRP3 and related inflammatory factors (46). Furthermore, these harmful substances also cause massive death of lung cells, lead to the release of a variety of endogenous dangerous molecules and further promote the activation of the NLRP3 inflammasome. The decrease of extracellular nucleotidase expression and the increase of ATP in patients with COPD further activates the NLRP3 inflammasome through the P2X7 receptor and ATP also promotes the activation of inflammatory cells through the P2X7 receptor, which aggravates the inflammatory reaction in the lung (47,48). At the same time, oxidative stress is another important mechanism of activation of the NLRP3 inflammasome. A large number of studies have found that during the occurrence and aggravation of COPD, the level of ROS in the lung is significantly increased and the infiltration of immune cells in the airway further increases the production of oxygen free radicals and oxidative stress in the lung, which has been confirmed in animal experiments. IL-1β production and confirmed cell infiltration were significantly inhibited in NLRP3 gene knockout mice. In addition, the activity of caspase-1 and the levels of inflammatory factors such as IL-1β and IL-18 in lung tissue of COPD patients was also significantly increased, suggesting that the NLRP3 inflammasome was indeed activated during the occurrence and development of COPD (49,50).

So far, there is little research on the role of NLRP3 inflammasome in the progression of COPD. Certain scholars have found that the specific expression of IL-1β in mouse lung epithelial cells leads to increased infiltration of macrophages and neutrophils in the lung, destruction of elastic fibers in the alveolar septum, fibrosis of the airway wall and dilatation of small airways at the distal end of the lung (51). In addition, overexpression of IL-18 increased the level of inflammation in the lungs of mice and promoted the formation of emphysema and pulmonary hypertension in mice. However, knocking out IL-1R or IL-18 and intervention with IL-1β neutralizing antibody significantly reduced lung injury and inflammatory reaction in mice (52). Similarly, application of caspase-1-specific inhibitors also reduced infiltration of inflammatory cells in the lung of mice and reduced the level of IL-1β (53). Furthermore, it has been observed that P2X7 receptor-specific inhibitors or knockout of P2X7 can inhibit the activation of caspase-1 and the release of IL-1β in a smoking-induced lung injury model in mice, thus alleviating the symptoms of COPD (54).

NLRP3 inflammasome involved in bronchial asthma

Bronchial asthma is a kind of airway hyperreactive chronic inflammation involving numerous cells and its main feature is extensive and variable reversible expiratory airflow restriction (55). It has been shown that asthma pathogens promote macrophages, epithelial cells and dendritic cells to release ATP, activate the NLRP3 inflammasome and enhance airway inflammation. In addition, high levels of ATP and P2X7 receptor were detected in the lungs of asthmatic patients (56). Inhalation of allergens is one of the important causes of asthma. Yazdi et al (57) found that allergens promote the production of ROS in the airways and ROS activates the NLRP3 inflammasome, thus increasing the maturity and release of IL-1β and IL-18. An associated study detected an increase in caspase-1 activity and IL-1β levels in a mouse asthma model induced by ovalbumin and alumina, and the IL-1β level was positively correlated with caspase-1 activity (58). In loss-of-function experiments, researchers found that neutralizing lung ATP or applying non-selective purinergic receptor antagonists reduced the infiltration of inflammatory cells and airway hyperresponsiveness in asthmatic mice induced by ovalbumin and alumina, and the application of caspase inhibitors also reduced airway inflammatory reaction in asthmatic mice (56,59). Overexpression of IL-1R antagonist by recombinant adenovirus or direct deletion of IL-1 may also significantly reduce the airway hyperresponsiveness caused by allergens in mice and alleviate inflammation around the airway (60,61). In clinical research, Harada et al (62) found that high levels of IL-1β can also be detected in the sputum of asthmatic patients, and it is positively associated with the severity of the disease.

Type 2 T-helper (Th2) cells are closely related to bronchial asthma, which increases airway reactivity of sensitizing eosinophils (63). Knocking out NLRP3 or caspase-1 inhibits the activation of Th2 cells and reduces airway eosinophils and factors related to the activation of Th2 cells. Accordingly, knocking out IL-1β or IL-R can also significantly inhibit the activation of Th2 cells, which proves that NLRP3 inflammatory corpuscles participate in the occurrence and development of bronchial asthma (64-66). IL-18 has been proved to promote Th2 cells to secrete IL-4, IL-5, IL-9 and IL-13. Lung-specific overexpression of IL-18 increases the infiltration of inflammatory cells such as T cells, eosinophils and neutrophils in the airway of asthmatic mice induced by ovalbumin and enhances airway hyperresponsiveness (67). On the contrary, knocking out IL-18 significantly alleviates asthma symptoms induced by allergens such as ovalbumin in mice (68). Of note, the NLRP3 inflammasome may not be involved in airway hyperresponsiveness caused by ovalbumin and Allen et al (69) also confirmed that knocking out NLRP3 did not affect airway allergic response of mice with four different allergic asthma models. Even Hartwig et al (70) found that IL-18 has nothing to do with the occurrence of asthma and can even inhibit the progress of asthma, which also shows that the role of the NLRP3 inflammasome in asthma requires further study.

Role of NLRP3 inflammasome in silicosis

Silicosis is one of the most important occupational diseases in the world, which is caused by crystalline silicon dioxide (SiO2) (71). In the whole disease development process of silicosis, NLRP3 inflammasome is involved and occupies a large proportion. Studies have shown that SiO2 can be used as an activating molecule to stimulate the assembly of NLRP3 and ASC in macrophages, promote the secretion of IL-1β under the mediation of caspase-1 and participate in the occurrence of diseases. At the same time, ROS produced by cells is also used as the upstream signal of the NLRP3 signaling pathway to activate the NLRP3 inflammasome. In subsequent animal experiments, Cassel et al (72) found that compared with wild-type mice, ASC−/− and NLRP3−/− mice had less lung inflammation and pulmonary fibrosis, which further confirmed that the NLRP3 inflammasome is involved in the development of silicosis. Jessop et al (73) also found that autophagy of macrophages can inhibit the activation of the NLRP3 inflammasome induced by SiO2 stimulation by chelating or degrading inflammatory corpuscles and cytokines, thus delaying the progress of subsequent diseases.

NLRP3 inflammasome is involved in the course of bacterial infectious pneumonia

Community-acquired and hospital-acquired infectious pneumonia are mainly caused by Staphylococcus aureus (74). It has been proved that α-hemolysin is the key virulence factor to induce lung inflammation, which has the function of activating the processing and secretion of IL-1β, and its function of inducing cell necrosis requires the signal transduction of NLRP3 inflammasome (75). Animal experiments have confirmed that NLRP3 inflammasome mediates α-hemolysin-induced lung injury. Compared with wild-type mice, NLRP3−/− mice have no decreased lung compliance and no obvious inflammatory reaction after being infected with pneumonia, which proves that NLRP3 inflammasome plays a role in mediating lung injury caused by pneumonia (76).

Streptococcus pneumoniae hemolysin is the main virulence factor of Streptococcus pneumoniae, which causes the formation of cavities on the cell surface and leads to cell lysis tissue damage (77). Furthermore, Streptococcus pneumoniae hemolysin can also interfere with the plasma membrane and cause K+ outflow, which further activates the NLRP3 inflammasome, triggering the secretion of IL-1β and IL-18, and leads to a series of downstream inflammatory reactions. It has been shown that IL-1β is necessary to resist pneumococcal infection and the production of IL-1β depends on NLRP3 inflammasome and TLR2; accordingly, the NLRP3 inflammasome is an important mediator of the innate immune response to pneumococcal infection (78,79). van Lieshout et al (80) also found that compared with wild-type mice, the levels of cytokines and chemokines expressed by NLRP3−/− mice decreased, among which the level of IL-1β decreased significantly and the animals died within 48 h after being infected with bacteremia, while wild-type mice only showed mild lung inflammation. It shows that NLRP3 plays a beneficial role in pneumonia caused by Streptococcus pneumoniae in the early stage (80). In short, the NLRP3 inflammasome is widely involved in the occurrence and development of bacterial infectious pneumonia.

NLRP3 inflammasome and digestive system diseases

As a part of the innate immune system, the NLRP3 inflammasome can be activated by various metabolic stimulation signals, among which the main effector molecules, IL-1β and IL-18, play an important role in the occurrence and development of digestive system diseases. As the key link of IL-1β- and IL-18-mediated inflammatory reaction, the NLRP3 inflammasome plays an essential role in the occurrence of digestive system diseases (Table II).

Table II

NLRP3 inflammasome and digestive system diseases.

Table II

NLRP3 inflammasome and digestive system diseases.

DiseaseRelated mechanism(Refs.)
Hp-related stomach diseasesHp infection may lead to the activation of intracellular NLRP3 inflammasome in gastric epithelial cells, mononuclear macrophages and lymphocytes, and then produce a large number of active IL-1β and IL-18 to induce diseases.(81-89)
Liver diseasesActivation of NLRP3 inflammasome in liver tissue can promote the production of active IL-1β and IL-18, and finally lead to the occurrence and development of liver fibrosis.(92-105)
Inflammatory intestinal diseasesActivation of NLRP3 inflammasome in intestinal mucosa or epithelial cells can promote the production of active IL-1β and IL-18, which leads to intestinal inflammation and hinder the repair mechanism of intestinal epithelium.(107-125)
Acute pancreatitis/ acute severe pancreatitisActivation of NLRP3 inflammasome in acinar cells leads to the massive production of IL-1β and IL-18, which eventually leads to inflammation and injury of the pancreas and peripancreatic tissues.(127-132)

[i] NLRP3, Nod-like receptor family pyrin domain containing 3; Hp, Helicobacter pylori.

NLRP3 inflammasome and Helicobacter pylori (Hp)-related stomach diseases

Hp is an aerobic gram-negative bacterium that causes gastric mucosal inflammation in the stomach. The infection rate of Hp was reported to be high and it has been colonized in the gastric epithelial cells of healthy individuals accounting for >50% of the world population (81). Hp infection is closely related to numerous kinds of stomach diseases and persistent Hp infection is related to complications such as chronic gastritis, ulcer and even gastric cancer, among which the relationship between Hp infection and gastric cancer has been studied the most. However, so far, the initiation of the pro-inflammatory signaling cascade in gastric epithelial cells caused by Hp infection has remained elusive and the specific pathogenesis of gastrointestinal diseases caused by Hp infection remains to be further studied (82). However, Pachathundikandi et al (83) have confirmed that the activation of the NLRP3 inflammasome and the production of a large number of pro-inflammatory factors, including IL-1β, are the key factors for the occurrence and development of Hp-related gastrointestinal diseases (83). Hp infection induces the production of various cytokines, which promotes the aggregation and infiltration of a series of immune cells, such as monocytes, macrophages and lymphocytes, into the gastric mucosa, thus leading to related gastric diseases. In this process, cytokines play the role of the initiator and IL-1β is one of the most critical cytokines (84-86). Caspase-1 is the key enzyme for the differentiation and maturation of IL-1β, and IL-1β can transform the precursor of IL-1β into mature IL-1β through its shearing action. However, the production of caspase-1 depends on the activation of the NLRP3 inflammasome. In this process, pro-caspase-1 is cleaved to form caspase-1 with biological activity, which leads to massive secretion of IL-1β and induces diseases (11,12). In a groundbreaking study, Kameoka et al (87) found that Hp infection leads to increased IL-1β secretion and this process is achieved through the NLRP3 inflammasome, which initially confirmed the possibility that Hp infection can induce gastric diseases by activating NLRP3 inflammasome. A clinical study on gastric cancer confirmed that Hp induces gastric cancer by activating the NLRP3 inflammasome in the mononuclear phagocyte system and promoting the release of inflammatory cytokines (87). Of course, this process can also be achieved by activating NLRP3 inflammasome in gastric mucosal epithelial cells GES-1 through ROS pathway or Hp toxin-related protein CagA (88). Of note, during the study of peptic ulcer disease induced by Hp infection, Davari et al (89) found that the decrease of IL-1β protein expression and the increase of NLRP3 expression promoted Hp to develop digestive tract ulcer. Therefore, it is of great significance to explore the mechanism of activation of the NLRP3 inflammasome in Hp-related stomach diseases to further the understanding of the prevention of Hp-related stomach diseases and even gastric cancer.

NLRP3 inflammasome and liver diseases

Liver disease has become a major global health problem. According to relevant surveys, millions of individuals worldwide die of liver disease every year. Liver diseases are mainly divided into nonalcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD), among which NAFLD is the most common chronic liver disease. Both NAFLD and ALD can lead to fibrosis and cirrhosis and increase the risk of hepatocellular carcinoma if they are not properly controlled (90,91). Wree et al (92) found that the NLRP3 inflammasome, pro-IL-1β, pro-IL-18 and pro-caspase-1 were significantly increased in the liver tissue of patients with NAFLD. In addition, NAFLD is often associated with obesity, type 2 diabetes and hyperlipidemia (93). Lee et al (94) found that NLRP3 and IL-1β are increased in peripheral blood mononuclear cells and serum of patients with type 2 diabetes. Furthermore, the expression of NLRP3 inflammasome was also increased in the liver tissues of obese patients and mice (95). In a further experimental study, it was found that the NLRP3 inflammasome may play different roles in the process of NAFLD developing into nonalcoholic steatohepatitis (NASH). In the early NAFLD animal model, increased NLRP3 inflammasome components in the liver was only observed at the mRNA level. However, after NAFLD completely developed into NASH, the mRNA and protein levels of NLRP3 inflammasome (caspase-1 and IL-1β) in the liver tissue and serum of the animal model increased significantly. In the reversal experiment of mice with NLRP3, ASC and caspase-1 gene deficiency, Csak et al (96) further confirmed that NLRP3 inflammasome did participate in the occurrence of NAFLD.

Excessive drinking and alcoholism are usually the direct causes of ALD (97). ALD and NAFLD have certain similarities in disease characteristics, both of which develop from liver degeneration to liver fibrosis, and may eventually develop into liver cancer (98). A clinical study showed that the levels of IL-1β, IL-18 and caspase-1 in the liver of patients with ALD were higher than those of healthy controls (99). Furthermore, in animal experiments, compared with the control mice, the protein levels of NLRP3 and IL-1β and caspase-1 activity in the liver of alcohol-fed mice were significantly enhanced, which was consistent with the clinical research conclusions (100). In addition, in the reverse experiment of mice with NLRP3, ASC and caspase-1 gene deletion, it was found that the degree of fat infiltration and damage in the liver of mice was reduced (100,101). Therefore, NLRP3 inflammasome is involved in the pathogenesis of ALD.

Hepatocirrhosis is the ultimate development trend of the above two kinds of liver diseases (102). Boaru et al (103) detected a high level of NLRP3 expression in the liver tissue of a mouse liver fibrosis model. In addition, in the mouse model with NLRP3 or ASC gene deficiency, the degree of liver fibrosis was weakened (104). Clinicians also found an increase of IL-1β, IL-18 and active caspase-1 in ascites macrophages of patients with hepatocirrhosis (105). Therefore, NLRP3 inflammasome is involved in the occurrence and development of numerous liver diseases, and effective intervention is likely to be a new strategy to treat these diseases.

NLRP3 inflammasome and inflammatory intestinal diseases

Inflammatory bowel disease (IBD) includes Crohn's disease and ulcerative colitis, and its main clinical features are recurrent abdominal pain, diarrhea and even mucus pus and bloody stool. If IBD cannot be effectively treated, it increases the risk of rectal cancer. Previous studies have found that the pathogenesis of IBD mainly includes genetic factors, environmental factors and immune factors, of which immune factors may be the most critical pathogenic factors, and inflammatory factors may play an important role (106). Previous studies have found high expression levels of IL-1β and IL-18 in the intestinal mucosa of patients with Crohn's disease and ulcerative colitis, allowing for the conclusion that the expression level of IL-1β or IL-18 may be related to the susceptibility to IBD (107-109). Further research indicated that NLRP3 was highly expressed in the early stage of IBD, and then the processing of pro-IL-18 and pro-IL-1β by caspase-1 led to an increase of pro-inflammatory factors IL-1β and IL-18, which eventually led to the aggravation of the course of IBD (110,111). By comparing the secretion of IL-1β in peritoneal macrophages of NLRP3 knockout mice and non-knockout mice, it was confirmed that NLRP3 inflammasome played a role in promoting the progression of the disease in the colitis model induced by dextran sulfate sodium (DSS) (112). Of note, animal studies also found that NLRP3 gene knockout mice are more susceptible to colitis induced by DSS than wild-type mice, and mice with ASC or caspase-1 gene deficiency also have the same susceptibility to colitis (113-115). These gene knockout mice have more serious intestinal pathological changes and higher mortality in the acute and chronic stages of DSS-induced colitis. This shows that the NLRP3 inflammasome may also play a certain role in the process of intestinal inflammatory reaction, which is characterized by the increase of stem cell division at the bottom of the crypt to replace damaged intestinal cells (116). Generally speaking, activation of the NLRP3 inflammasome leads to a large number of secretion traps of IL-1β and IL-18, which hinders the intestinal repair mechanism, increases the permeability of the intestinal epithelium and eventually leads to the deterioration of the disease.

If IBD develops into chronic inflammation, it becomes an important cause of IBD-related intestinal tumors (e.g. colon or rectal cancer) (117). According to reports, IL-1β is not only a proinflammatory factor, but also a cancer-promoting factor (118). A high-cholesterol diet increases the risk of colon cancer. Du et al (118) found that cholesterol crystals promote inflammation and tumor development in the intestine of a mouse colon cancer model. Furthermore, cholesterol crystallization can activate the NLRP3 inflammasome, leading to an increase of IL-1β secretion to promote the development of colon cancer. In addition, it was found that knocking out the NLRP3 gene reversed this process, which also preliminarily confirmed that the NLRP3 inflammasome-related pathway did participate in the course of IBD-related tumors (118). However, IL-18, another downstream inflammatory factor of the NLRP3 inflammasome, may have a role in inhibiting the progression of the disease. Studies have found that IL-18 plays an anti-tumor role in several experimental tumor models of sarcoma and melanoma (119-121). IL-18 can not only inhibit tumor angiogenesis, but also promote the repair and regeneration of ulcer epithelium (122,123). It has been indicated that, although IL-18 can repair colon epithelial injury by promoting the proliferation of intestinal cells, it inhibits proliferation in the chronic stage of colitis, so IL-18 may play an important role in preventing and inhibiting IBD-related tumors (124,125). In a word, the NLRP3 inflammasome is closely related to IBD and IBD-related tumors, and further study of its specific mechanism may be helpful in treating these diseases.

NLRP3 inflammasome and acute pancreatitis (AP)/acute severe pancreatitis (SAP)

AP is one of the most common acute abdominal conditions in the clinic and it is also the most common digestive system disease in patients. As a classic inflammatory disease, patients usually have the main clinical features of elevated serum amylase and lipase. >20% of AP is SAP (126). SAP has an acute onset and rapid development, which easily leads to multiple organ failure, with a mortality rate of >20% (127). The essence of pancreatic inflammation is that acinar cells secrete a large number of inflammatory factors after being damaged to trigger the inflammatory process. These inflammatory factors also lead to the recruitment and activation of neutrophils and monocytes, thus releasing oxidants and cytotoxic substances, further damaging pancreatic tissue (127). Various inflammatory factors have been proved to be important indexes to evaluate the severity of AP and IL-1β and IL-18 are among them (128). Different from other inflammatory factors, IL-1β and IL-18 are synthesized as precursor proteins and need to be cleaved to produce their bioactive forms, and it has been speculated that NLRP3 inflammasome may be involved in this process. Fu et al (129) found that the inflammatory corpuscles of NLRP3 were obviously activated during AP in mice, and in further experiments, they found that the edema and inflammation of pancreatic tissue in mice were obviously reduced in the absence of caspase-1, ASC or NLRP3. It has also been confirmed that the secretion and maturation of IL-1β in the AP model of mice with NLRP3 gene deficiency are obviously inhibited, which also impairs the further development of the AP inflammatory cascade (129). Studies also found that TLR4 can aggravate the development of AP by mediating the activation of the NLRP3 inflammasome (130,131). Therefore, NLRP3 inflammasome may be involved in the occurrence and development of AP.

Similarly, in SAP, inflammatory reaction of the pancreas and peripancreatic tissues is mainly caused by local proinflammatory factors such as IL-1β, and the production of mature IL-1β is completed by the shearing process of caspase-1, and the biological activity of caspase-1 is obtained on the basis of the formation of NLRP3 inflammasome. In an animal model of SAP, Ren et al (132) found that the expression of various components of NLRP3 inflammasome increased, which in turn promoted the activation of caspase-1 and eventually led to the production of proinflammatory factors such as IL-1β, which caused damage to the pancreas and peripancreatic tissues and participated in the occurrence and development of SAP (132).

NLRP3 inflammasome is involved in bone and joint system diseases

With the continuous progress in the research on the structure and function of NLRP3 inflammasome, increasing evidence shows that the NLRP3 inflammasome is a key factor mediating tissue injury in numerous bone and joint diseases, and its pro-inflammatory factor release and cell apoptosis effect can aggravate bone and joint injury. Various studies have confirmed that NLRP3 has an important role in common diseases such as osteoarthritis and certain autoimmune-related orthopedic diseases. The NLRP3/caspase-1/IL-1β/IL-18 axis is a good target for the treatment of bone and joint diseases (Table III).

Table III

NLRP3 inflammasome is involved in bone and joint system diseases.

Table III

NLRP3 inflammasome is involved in bone and joint system diseases.

DiseaseRelated mechanism(Refs.)
Rheumatoid arthritisAfter synovial tissue is stimulated, the NLRP3 inflammasome can be activated through NF-ĸB signaling pathway or HIF-1α-related pathway, thus promoting the production of IL-1β and finally causing the destruction of synovial tissue of joints.(134-143)
OsteoarthritisActivation of the NLRP3 inflammasome in articular chondrocytes or macrophages and monocytes induces the activation and release of IL-1β and IL-18, which eventually leads to degenerative diseases of articular cartilage.(144-149)
OsteoporosisNLRP3 inflammasome in osteoclasts can directly regulate osteoclast activity through proteolysis, and NLRP3 inflammasome may also thicken chondrocyte maturation and osteoblast activity, thus increasing the risk of osteoporosis.(151-157)
Gouty arthritisStimulators such as uric acid crystals activate NLRP3 inflammasome, which leads to an increase in the expression of pro-inflammatory cytokines IL-1β and IL-18, and finally leads to joint swelling and pain.(159-163)
Intervertebral disc degenerationMitochondrial dysfunction, endoplasmic reticulum stress and ROS damage can activate the NLRP3 inflammasome and finally lead to increased release of IL-1 and other factors, which in turn leads to disc degeneration.(165-167)

[i] NLRP3, Nod-like receptor family pyrin domain containing 3; HIF, hypoxia-inducible factor; ROS, reactive oxygen species.

Role of NLRP3 inflammasome in rheumatoid arthritis (RA)

RA is an autoimmune disease characterized by joint injury. The initial pathological manifestation is synovitis. With the development of the disease, synovitis can invade cartilage and bone, which may lead to irreversible joint malformation and dysfunction. The pathogenesis of RA is mainly related to rheumatoid factor and anti-citrulline protein antibody (133).

Studies have shown that the NLRP3 inflammasome may have a role in the pathogenesis of RA. NLRP3 and ASC were expressed in myeloid cells, endothelial cells and lymphocytes of patients with RA, but the expression level of NLRP3 did not increase in fibroblast-like synovial cells (134,135), and it also increased in peripheral blood cells of patients with RA (136). Zhang et al (137) also found that the expression of NLRP3 in the serum and synovium of mice with collagen-induced arthritis (CIA) was significantly higher than that of the control group and the expression of NLRP3 in the synovium of the articular capsule was positively associated with the severity of CIA/disease imaging score in mice. A further study indicated that the expression of NLRP3 inflammasome in synovium was obviously inhibited and its clinical symptoms were alleviated after Guo et al (138) used NLRP3-specific inhibitors on CIA model mice. The expression of caspase-1 in vivo was downregulated and IL-1β in synovium and serum of joints was significantly decreased.

When cells are stimulated to a certain extent, the NF-ĸB pathway is activated and they can enter the stage of activation of the NLRP3 inflammasome. Therefore, targeting the NF-ĸB pathway may have potential therapeutic effects on NLRP3-related diseases. A20, TNF-α-inducible protein 3 is a kind of protein involved in the negative feedback regulation of NF-ĸB signaling and is also considered a susceptible gene of RA. A20 knockout mice show spontaneous erosive arthritis related to the increase of NLRP3 inflammasome and the secretion of IL-1β (139). A20-deficient bone marrow-derived macrophages secreted inflammatory factors and apoptosis related to the overactivation of NLRP3, which indicated that A20 could inhibit RA by weakening the activation of NLRP3 inflammasome (140).

The imbalance of microRNA (miR) in synovial cells and synovial fluid and hypoxia microenvironment in synovium also have an important role in the occurrence and development of RA diseases. Li et al (141) found that miR-20a can reduce the production of ROS introduced by thioredoxin binding protein (TXNIP) and the activation of NLRP3 inflammasome by targeting the 3′-UTR of rat TXNIP. In further animal experiments, it was found that the RA rat model could be improved by receiving miR-223 from exosomes, and the related mechanism may be that miR-223 can target the 3′-UTR of NLRP3 and inhibit the expression of NLRP3 (142). The hypoxia environment in the synovium may also induce the activation of NLRP3. In the rat model, synovial succinate accumulates and activates NLRP3 inflammasome by regulating the transcription of hypoxia-inducible factor-1α (HIF-1α), and the level of HIF-1α is increased in fibroblast-like synoviocytes of patients with RA (143). Therefore, the NLRP3 inflammasome can be activated by various upstream signals and its expression tends to increase in patients with RA or animal models, thus participating in the occurrence and development of RA diseases. Therefore, targeting NLRP3 shows a good therapeutic prospect, which effectively inhibits the secretion of downstream inflammatory factors and apoptosis.

Role of NLRP3 inflammasome in osteoarthritis (OA)

OA is a degenerative joint disease whose main symptom is joint pain. The etiology is still unclear, and the pathological manifestations are mainly deformation and destruction of articular cartilage fibrosis. Numerous inflammatory factors induce local synovitis and cartilage matrix degradation and then promote the progress of knee OA. The expression of NLRP3, ASC and caspase-1 in synovial tissue of patients with knee OA is increased. In early in vitro experiments, Han et al (144) found that knocking out NLRP3 could weaken inflammation and apoptosis of synovial cells induced by LPS and ATP.

Alkaline calcium phosphate and calcium phosphate crystals usually exist in synovial fluid and tissues of patients with OA and play an important role in the pathogenesis of OA (145). Both alkaline calcium phosphate and calcium phosphate crystals can activate NLRP3 inflammasome, and alkaline calcium phosphate promotes the production of IL-1β by macrophages and monocytes by activating the NLRP3 inflammasome (146). It is well-known that IL-1β and IL-18 in synovial fluid are positively related to the severity of OA (147). In a mouse OA model experiment, oral selective NLRP3 inflammasome inhibitor obviously improved the inflammation of mouse joint tissue and the inflammatory factors in the synovium tissue of the control mice were obviously reduced, which indicates that targeting NLRP3 can also improve the progress of OA diseases (148).

In the chondrocyte OA model stimulated by IL-1β, Senkyunolide A (SenA) inhibited the pathway of NLRP3 inflammasome and significantly reduced the expression of related proteins, such as NLRP3 and ASC. It was found that SenA inhibits the NLRP3 signaling pathway of chondrocytes in an OA model stimulated by IL-1β and OA mice (148). Further clinical drug research found that metformin, a first-line treatment drug for diabetes, has similar effects, which has attracted much attention for its future prospects in OA treatment. Lordén et al (149) performed medial meniscus instability surgery on the knee joint of experimental mice to build a mouse model of OA and the experimental group of mice received metformin intervention. After administration, the researchers found that the expression of NLRP3, caspase-1, IL-1β and other related factors in mouse articular cartilage decreased significantly. In addition, at the subchondral bone level, metformin can inhibit the formation of osteophytes, increase bone density and reduce trabecular separation. Therefore, metformin can inhibit the activation of NLRP3 inflammasome and the focal death of chondrocytes, thereby delaying the progress of OA (149).

As the most common degenerative disease of joints, OA is characterized by degenerative changes of articular cartilage. The characteristics of releasing inflammatory factors and promoting apoptosis of NLRP3 are closely related to the pathological changes of OA such as synovitis and chondrocyte apoptosis, and accordingly, targeting NLRP3 has the potential to delay the progress of OA.

NLRP3 inflammasome involved in osteoporosis (OP)

OP is a systemic metabolic bone disease characterized by decreased bone mass and destruction of the bone microstructure, which leads to increased bone fragility and easy fracture (150). There are numerous factors leading to OP. According to certain scholars, the NLRP3 inflammasome may play an important role in this process. In a previous study, Alippe et al (151) found that NLRP3 deficiency can prevent bone loss caused by ovariectomy (OVX) in mice and play an important role in bone resorption. In vivo studies of NLRP3 gene knockout mice showed that NLRP3 participated in bone induction; NLRP3 knockout mice are shorter than normal mice and this growth defect is mainly characterized by growth plate defect and osteopenia of trabecular bone. The researchers speculated that this effect is achieved by regulating the maturation of hypertrophic chondrocytes and the activity of osteoblasts (152). Recently, Jiang et al (153) also found that NLRP3 inflammasome can cause dysfunction of osteoclasts by reducing differentiation, and at the same time accelerate the proliferation and differentiation of osteoclasts, which promotes bone absorption and destroys bone formation. NLRP3 inflammasome in myeloid cells indirectly regulates the activity of osteoclasts through systemic inflammation, while NLRP3 inflammasome in osteoclasts directly regulates the activity of osteoclasts through proteolysis of poly(ADP-ribose) polymerase 1, which is a negative regulator of osteoclast formation. Inhibition of the NLRP3 inflammatory corpuscle pathway promoted osteoblast differentiation and restored bone volume in OVX mice (154,155). The involvement of NLRP3 inflammatory corpuscles in the course of OP has also been preliminarily confirmed in clinical research. Guaraná et al (156) 's research on menopausal women with OP showed that NLRP3 inflammatory corpuscles activate pro-inflammatory cytokines IL-1β and IL-18, and the single nucleotide variation caused by NLRP3 inflammasome is closely related to the severity of OP. Therefore, NLRP3 inflammasome not only accelerates bone resorption, but also inhibits bone formation, thus increasing the risk of OP (157). Therefore, inhibiting NLRP3 inflammasome is a promising therapeutic strategy to prevent and control OP.

Relationship between NLRP3 inflammasome and gouty arthritis (GA)

GA is a disease in which the amount of uric acid in the body increases due to excessive purine metabolism or insufficient uric acid excretion, which leads to the crystallization and accumulation of uric acid in joints, thus leading to joint pain and swelling (158). As the upstream pathway of IL-1β and IL-18, NLRP3 inflammasome is firstly activated by uric acid crystallization and LPS in this process, and the self-activation of caspase-1 is mediated by the activated NLRP3 inflammasome, which leads to the increased expression of pro-inflammatory cytokines IL-1β and IL-18 (159). It is reported that calcium pyrophosphate dihydrate (CPPD) crystals cause pseudo-RA attack and participate in the activation of NLRP3 inflammasome. Zhao et al (160) confirmed that the deposition of monosodium urate (MSU) crystals can lead to inflammatory reaction of human macrophages, which is the classic pathogenesis of acute gout. Macrophage phagocytosis of MSU crystals activates NLRP3 inflammasome and then upregulates the expression of IL-1β and IL-18, thus inducing the occurrence of acute GA (160). In addition, inhibiting the activation of NLRP3 inflammasome can prevent acute GA, and therefore, it is thought that the activation of NLRP3 inflammasome is the core process of gout attack (161,162). Blocking the activation of NLRP3/caspase-1/IL-1β pathway induced by ATP has a significant effect on relieving GA inflammation in rats (163). Therefore, inhibiting the activation of NLRP3 inflammasome and promoting the relief of RA inflammation represent a new direction in the treatment of GA.

NLRP3 inflammasome induces intervertebral disc degeneration (IDD)

IDD is an age-related degenerative disease of the spine, which has a great influence on social economy and human life. It is also one of the main causes of low back pain, which can cause serious nerve damage and disability. The main pathological changes are the decrease of proteoglycan content, height, endplate sclerosis and osteophyte formation, which eventually leads to a decrease of the ability of the intervertebral disc to withstand compression load (164). The pathogenesis of IDD is complex and the efficacy of current treatments is not obvious, and accordingly, it is urgent to find new therapeutic targets. It has been indicated that during the occurrence and development of IDD, NLRP3 inflammasome may be activated, thus mediating the production of a variety of inflammatory cytokines and further promoting the progress of IDD. A study also showed that this process may depend on NLRP3′s ability to perceive change in intracellular homeostasis, the activation of NLRP3 inflammasome, mitochondrial dysfunction related to IDD, endoplasmic reticulum stress and ROS damage (165). At the same time, this study also confirmed that the NLRP3 inflammasome participated in the inflammatory reaction of IDD mice. The researchers found that, compared with normal rat intervertebral disc tissues, the expression of NLRP3, caspase-1 and IL-1 in degenerated intervertebral disc were significantly upregulated and the expression of caspase-1 and IL-1 was similar (165,166). In further research, Zhao et al (167) found that the lactic acid content in intervertebral disc tissue increased during IDD, thus stimulating nucleus pulposus cells to drive the activation of NLRP3 inflammatory bodies and increase the release of IL-1β, which further induced the IDD process, which they thought was realized through ROS and NF-κB-related pathways. These findings fully indicate that NLRP3 inflammatory corpuscles may play an important role as a potential target for IDD treatment in the future.

NLRP3 inflammasome participates in cardiovascular diseases

The NLRP3 inflammasome is a protein complex that can be activated by crystal or granular PAMPs and ischemic hypoxia risk-related molecular patterns, DAMPs, which promote the secretion of IL-1β and IL-18. Through these mechanisms, it can promote diseases such as atherosclerosis and heart failure. Therefore, NLRP3 inflammasome may have a key role in the physiology and pathology of cardiovascular diseases and play the role of pro-inflammatory mediators. In recent years, it has become one of the focuses of relevant research (Table IV).

Table IV

NLRP3 inflammasome participates in cardiovascular diseases.

Table IV

NLRP3 inflammasome participates in cardiovascular diseases.

DiseaseRelated mechanism(Refs.)
AtherosclerosisThe activation of NLRP3 inflammasome in arterial tissue leads to the increase of IL-1β expression, which in turn leads to the early inflammatory reaction of AS.(169-173)
Heart failureThe activation of NLRP3 inflammasome in myocardial cells can lead to a large amount of secretion of IL-1β and IL-18, which will lead to cardiac contraction dysfunction and myocardial cell death, which may eventually lead to ventricular remodeling.(174-180)
Myocardial ischemia-reperfusion injuryThe outflow of ROS and K+ mediates the activation of NLRP3 inflammasome in myocardial fibroblasts or microvascular endothelial cells, which leads to the increase of IL-1β and IL-18, and finally induces myocardial apoptosis and myocardial infarction.(181-183)

[i] NLRP3, Nod-like receptor family pyrin domain containing 3. AS, atherosclerosis; ROS, reactive oxygen species.

NLRP3 inflammasome and atherosclerosis (AS)

AS is a chronic inflammatory disease and it is also one of the most important causes of death from cardiovascular diseases. The pathogenesis of AS is closely related to inflammatory reaction and lipid accumulation, but the specific pathogenesis of AS has not been fully clarified, and its prevention and treatment are limited (168). In 2010, researchers proposed for the first time that the NLRP3 inflammasome may be involved in the occurrence and development of AS. Duewell et al (169) believed that oxidized low-density lipoprotein could promote cholesterol crystallization, and then cholesterol crystallization activated NLRP3 inflammasome AS and endogenous signaling molecules, which eventually led to the increase of IL-1β expression, which was also the reason for the early inflammatory reaction of AS. In subsequent clinical experiments, Paramel Varghese et al (170) also found that the expression levels of NLRP3, ASC, IL-1 β and IL-18 mRNA in atherosclerotic plaques of patients with AS were significantly higher than those in normal arterial tissues. In the AS model of mice, Usui et al (171) found that compared to the control mice, the area of aortic plaque was significantly reduced after caspase-1 knockout, and the number of macrophages and vascular smooth muscle cells in the plaque and the level of plasma inflammatory factors were also reduced (171). At the same time, silencing the expression of the NLRP3 gene inhibited the progress of AS and the expression of inflammatory cytokines, reduced the contents of macrophages and lipids in plaques and promoted the stability of plaques (172). A previous clinical study confirmed that the levels of NLRP3 mRNA, IL-1β and IL-18 in peripheral blood mononuclear cells of patients with coronary heart disease were higher than those of patients without coronary heart disease and atorvastatin was observed to reduce the levels of IL-1β and IL-18 through the NLRP3 inflammasome to treat AS (173). Therefore, the NLRP3 inflammasome may be a potential target for the prevention and treatment of AS. Further clarifying the role of the NLRP3 inflammasome in AS and developing inhibitors of NLRP3 inflammasome are expected to provide new intervention measures for the prevention and treatment of AS.

Relationship between NLRP3 inflammasome and heart failure

Heart failure is a group of clinical syndromes caused by the impairment of ventricular filling and ejection function caused by structural or functional diseases of the heart. In the last decade, great progress has been made in drug treatment of heart failure, but its main pathogenesis has not been fully explained, so most patients still suffer from symptoms such as dyspnea and decreased fatigue tolerance. Previous studies have suggested that the NLRP3 inflammasome has an important role in regulating chronic inflammation and influencing heart failure (174).

Researchers have found that NLRP3, pro-caspase-1 and serum IL-1β in heart failure mice are significantly higher than those in the control group. However, after the NLRP3 gene is knocked out or NLRP3 inhibitor is given, the myocardial inflammatory response and myocardial contraction function of heart failure mice are significantly improved and the heart failure mice can also gain similar effects after applying IL-1β inhibitor (175). In further cell research, Mezzaroma et al (176) found that the related components ASC and caspase-1 of the NLRP3 inflammasome in myocardial cells of mice with heart failure were higher than those in the sham-operated group, which further confirmed that NLRP3 inflammasome could mediate the death of myocardial cells and lead to ventricular remodeling, and promote the occurrence of heart failure after myocardial infarction.

IL-1β, an inflammatory factor produced by the activation of NLRP3 inflammasome, can cause myocardial reversible systolic dysfunction, and its mechanism is to induce the activation of IL-18, which leads to cardiac systolic dysfunction (177,178). Clinicians have translated these research achievements to clinical treatment. For instance, anakinra, an antagonist of IL-1R, can alleviate the inflammatory reaction after myocardial infarction in patients with heart failure (179,180). IL-1β and IL-18 produced by activation of NLRP3 inflammasome are the focus of immunotherapy for heart failure at present. Immunosuppressants, such as anakinra, have shown good application prospects in clinical research, and NLRP3 inflammasome and their products will become new targets of immunotherapy for heart failure in the future.

Relationship between NLRP3 inflammasome and myocardial ischemia-reperfusion injury

Myocardial ischemia-reperfusion injury is a common pathophysiological process in ischemic cardiomyopathy, cardiopulmonary bypass and heart transplantation. Its mechanism includes free radical damage, Ca2+ overload, energy metabolism disorder and inflammatory reaction. Kawaguchi et al (181) have suggested that NLRP3 inflammasome may also be involved in this process. The release of IL-1β, the infiltration of inflammatory cells and the expression of inflammatory cytokines in myocardial tissue of mice with myocardial injury and ischemia-reperfusion increased, which was caused by the activation of NLRP3 inflammasome of myocardial fibroblasts mediated by ROS and K+ outflow (181). After establishing the model of myocardial ischemia in mice, researchers found that the expression of NLRP3, IL-1β and IL-18 mRNA in mouse myocardial fibroblasts increased significantly, while the heart function of NLRP3-related gene knockout mice improved significantly (181-183). In myocardial microvascular endothelial cells of mice with myocardial ischemia, the expression of NLRP3 increased, the activity of caspase-1 increased, and the production of IL-1β and IL-18 increased (183). Cardiac myocyte apoptosis and cardiac function were significantly improved after intracardiac injection of NLRP3 inhibitor (183). Furthermore, Kawaguchi et al (181) found that the inflammatory reaction, infarct size and degree of myocardial fibrosis in mice with myocardial ischemia were significantly reduced after silencing ASC or caspase-1 gene expression.

A large number of inflammatory mediators are being released during myocardial ischemia, which mediates the cascade amplification effect of inflammatory reactions. It has been proved that NLRP3 inflammasome plays an important role in myocardial ischemia. However, its specific signaling pathways and mechanisms require to be further clarified. It has a good research prospect to prevent and treat myocardial ischemia-reperfusion injury with NLRP3 inflammasome as the target.

Relationship between NLRP3 inflammasome and central nervous system diseases

In recent years, with the deepening of the research on NLRP3 inflammasome, its role in nervous system diseases has been increasingly studied. Although there have been numerous studies on nervous system diseases and inflammatory factors, research on the relationship between nervous system diseases and NLRP3 inflammatory corpuscles is still in its infancy. It is of great significance to clarify the pathogenesis of central nervous system diseases and improve the therapeutic effect to find out the specific function and relationship between them. Therefore, the role of NLRP3 inflammasome in common nervous system diseases was summarized in the following chapter (Table V).

Table V

Relationship between NLRP3 inflammasome and central nervous system diseases.

Table V

Relationship between NLRP3 inflammasome and central nervous system diseases.

DiseaseRelated mechanism(Refs.)
Traumatic brain injuryThe specific mechanism remains to be fully elucidated. NLRP3 inflammasome in neurons, astrocytes and microglia was activated in large quantities after brain injury, which induced neuroinflammatory reaction and neuronal death.(185-188)
PDThe specific mechanism remains to be fully elucidated. The activation of NLRP3 inflammasome in microglia of patients with PD and PD mouse models may be related to the occurrence and development of PD.(191,192)
Alzheimer's diseaseThe activation of NLRP3 inflammasome in brain tissue may enhance Aβ aggregation and promote the development of neuroinflammation and Tau lesions.(195-198)
MSNLRP3 inflammasome in MS plaque may be activated to promote the production of IL-1β and caspase-1, eventually leading to a series of neuropathy.(200)
Cerebral ischemiaAfter cerebral ischemia, NLRP3 inflammasome is activated and pro-inflammatory factors IL-1β and IL-18 are produced to aggravate the neuroinflammatory response.(202-206)

[i] NLRP3, Nod-like receptor family pyrin domain containing 3; PD, Parkinson's disease; MS, multiple sclerosis.

NLRP3 inflammasome participates in traumatic brain injury (TBI)

TBI is one of the most serious diseases of the nervous system in the world, which is usually caused by external forces, such as normal brain function damage or pathological brain tissue damage. Due to the irreversible loss of functional neurons and nerve tissue damage, the central nervous system is difficult to repair and regenerate after trauma, resulting in poor prognosis for patients with TBI. To date, the mechanism of TBI has not been thoroughly studied, so although a large number of successful preclinical studies have been used for TBI treatment, they are rarely used in transformation (184).

After TBI, neuroinflammation is a key factor that obviously aggravates brain tissue damage and leads to functional defects. It has been confirmed that inflammatory corpuscles have an important significance in regulating the secondary injury of TBI. A variety of inflammatory corpuscles that damaged brain tissue, particularly NLRP3, were detected in neurons, astrocytes and microglia, which can induce neuroinflammatory reaction and neuron death, aggravate brain tissue damage and was closely related to the pathogenesis of TBI (185). It has been shown that the gene and protein levels of the NLRP3 inflammasome are obviously upregulated after moderate TBI (186). It was also found that the level of NLRP3 in cerebrospinal fluid increased on the first day after brain injury in infants, decreased the next day and increased again at 3-4 days. Wallisch et al (187) indicated that the early increase of NLRP3 may be due to cell necrosis or traumatic dissolution, while the late increase may be due to infection, cell stress or activation of other inflammatory bodies. The NLRP3 inflammasome is activated after brain injury and scholars have found that inhibiting the activation of the NLRP3 inflammasome reduced inflammation and improved neurological function in brain injury model mice. Geng et al (188) observed that a high concentration of oxygen can inhibit the activation of the NLRP3 inflammasome and the inflammatory response after traumatic brain injury in mice. It should be noted that hypoxia therapy is a classic treatment for TBI, which indicates that the NLRP3 inflammasome is involved in the occurrence and development of TBI, and its inhibitors are likely to be a new important treatment for TBI.

Role of NLRP3 inflammasome in Parkinson's disease (PD)

PD is a progressive chronic neurodegenerative disease with a complex pathogenesis, which is closely related to numerous pathogenic factors, such as oxidative stress, neuroinflammation and mitochondrial dysfunction. At present, levodopa, dopamine receptor agonist and anticholinergic drugs are the main drugs used to treat PD in the clinic, but there are no clear treatment methods to improve the pathological progress (189). Studies have shown that the activation of microglia and neuroinflammation may be the key regulatory factors for the loss of dopaminergic neurons in PD. The activation of microglia in the brain and excessive release of proinflammatory mediators can lead to the expression of costimulatory molecules, which leads to neuroinflammation and nerve dysfunction (190). It has been found that the activation of NLRP3 inflammasome and the increase of ASC expression can be observed in microglia of patients with PD and PD mouse models. In PD mice, daily oral administration of NLRP3 inhibitor had a neuroprotective effect, reducing the loss of dopamine in the striatum and the deformation of dopaminergic substance in the substantia nigra (191,192). These studies show that the NLRP3 inflammasome has an important relationship with the occurrence and development of PD, but at present, only a small number of studies on this topic are available. Further study on the relationship between microglia, NLRP3 inflammasome and PD will lay a foundation for further elucidating its pathogenesis.

Role of NLRP3 inflammasome in AD

AD is a chronic and progressive neurodegenerative disease caused by numerous factors. Its main pathological features include amyloid β protein (Aβ) deposition, Tau protein hyperphosphorylation and neuronal loss. At present, AD has become a major disease that seriously endangers human health all over the world, but with the current treatment methods, it cannot be cured and these methods have toxic side effects (193,194).

According to Abbott (195), the NLRP3 inflammasome has an important role in the pathogenesis of AD. It can stimulate the innate immune response to trigger the inflammatory response, release the pro-inflammatory factors IL-1β and IL-18, and continue to activate during the occurrence and development of the disease, leading to neurological dysfunction and neuronal apoptosis (195). The NLRP3 inflammasome can regulate the activation of caspase-1 and increase the expression of IL-1β and IL-18 in AD brain tissue, which is related to the occurrence and development of diseases (196). The NLRP3 inflammasome has been proved to be co-located with amyloid plaques and its level is significantly increased in the brains of patients with AD. Activation of the NLRP3 inflammasome can enhance the aggregation of Aβ by weakening the phagocytosis of Aβ by microglia, and promote the development of neuroinflammation and Tau lesions. It has been reported in the literature that the NLRP3 inflammasome was significantly activated after Aβ was added to cultured astrocytes, and it was confirmed by experiments that the phosphorylation level and pathological features of Tau decreased significantly after Aβ was injected into the brain of ASC- or NLRP3-deficient mice, indicating that Aβ-induced Tau lesions were dependent on the NLRP3 inflammasome (197). Of note, certain researchers found that loss of NLRP3 and the subsequent activation of inflammatory corpuscles did not significantly affect the distribution of microglia in Aβ-related pathological reactions. It was indicated that the NLRP3 inflammasome did not play a significant role in forming microglia activation or driving Aβ-induced neurodegeneration (198). Therefore, although its role in the pathogenesis of AD is controversial, targeting the NLRP3 inflammasome is likely to become a potential treatment for AD.

Role of the NLRP3 inflammasome in multiple sclerosis (MS)

MS is an autoimmune disease of the central nervous system, which is characterized by inflammatory cell infiltration, neuronal degeneration, axonal injury and reactive glial hyperplasia. The causes and mechanisms of the disease have not been fully clarified, and it is generally thought that it is the result of multiple factors, such as genetic susceptibility, environment, viral infection and immunity (199).

Inoue et al (200) found that peripheral immune cells could enter the nervous system through the damaged blood-brain barrier during the pathological process of MS. IL-1β and caspase-1 are present in MS plaques and the expression of these proteins in peripheral blood mononuclear cells of patients with MS is also increased. Experimental autoimmune encephalomyelitis (EAE) is an ideal animal model of MS and numerous studies have confirmed that the NLRP3 inflammasome has an important role in EAE. In mice with silenced expression of the NLRP3 gene, the severity of pathological changes was reduced, the proliferation of astrocytes and the infiltration of inflammatory cells were reduced, and the symptoms were improved (200). The above research indicates that the neuroprotective effect of inhibiting inflammasome activation of NLRP3 in MS may provide a new breakthrough for the effective treatment of MS, and exploring drugs and methods to inhibit inflammasome activation of NLRP3 will provide new hope for the effective treatment of MS.

Role of NLRP3 inflammasome in cerebral ischemia

Cerebral ischemia is a destructive cerebrovascular disease, which is highly associated with neurological dysfunction, cognitive dysfunction and severe brain injury. The mechanism of its occurrence and development has been proved to be closely related to neuroinflammation, which is the main factor of secondary brain damage after cerebral ischemia (201).

At present, the clinical efficacy of treating cerebral ischemia is limited and its pathogenesis needs further discussion. As an important mediator of neuroinflammatory response after cerebral ischemia, NLRP3 mediates nerve cell injury and neuroinflammatory response, and linker ASC and effector protein caspase-1 are important components of the NLRP3 inflammatory complex. It has been shown that the expression levels of ASC and caspase-1 increase significantly after cerebral ischemia, which plays an important role in regulating the maturation and differentiation of IL-1β and IL-18 (202). Therefore, Wang et al (203) preliminarily concluded that the NLRP3 inflammasome produced proinflammatory factors IL-1β and IL-18 after cerebral ischemia. In animal experiments, researchers found that NLRP3-selective inhibitor MCC950 blocked the activation of NLRP3 inflammasome that can relieve cerebral ischemia-reperfusion injury (203), and previous studies have confirmed that TLR4 is an important mediator of neuroinflammatory cascade reaction in the central nervous system, which activates the NF-ĸB pathway to promote the transcription of NLRP3 components, and further regulates the release of downstream inflammatory mediators through inflammatory reaction. Subsequent studies further confirmed that cerebral ischemia can induce high-level phosphorylation of TLR4, NLRP3 and NF-ĸB (204,205). These findings indicate that NLRP3 inflammasome plays an important role in the pathogenesis of cerebral ischemia, and inhibiting the activation of NLRP3 inflammasome may provide new ideas for the treatment of cerebral ischemia (206).

Study of the NLRP3 inflammasome in clinical treatment

Abnormal activation of NLRP3 inflammasome will drive the occurrence and development of inflammatory diseases in numerous systems, so the NLRP3 inflammasome provides important targets for the treatment of these inflammatory diseases, and inhibiting the activity of the NLRP3 inflammasome is an important strategy to alleviate these inflammatory diseases. Scientists have found numerous biological inhibitors that can prevent the activation of NLRP3, and found that direct NLRP3 protein inhibitors have obvious advantages and good therapeutic potential compared with other types of inhibitors. However, there are no clinical drugs specifically targeting the NLRP3 inflammasome at present. Although related inhibitors have entered the clinical trial stage, their safety and effectiveness need to be further verified and there is still a lot of work to be done before their clinical application. Certain studies have made great breakthroughs in gene therapy. MiRNA and gene editing have become important in the study of this disease. A series of research results have proved that gene therapy can improve the course of this disease, but these methods have not yet entered the clinical trial stage. Therefore, it is of far-reaching significance to find an NLRP3 inflammasome inhibitor or gene editing method that can effectively treat NLRP3-related diseases with high efficiency, specificity and safety.

NLRP3 inflammasome inhibitors

Components of the complex signaling cascade during the activation of the NLRP3 inflammasome are being targeted to inhibit NLRP3 inflammasome. According to current development strategies, these inhibitory effects can be mainly divided into indirect inhibitors, direct inhibitors and protein inhibitors related to NLRP3 inflammasome (Table VI).

Table VI

Classical inhibitors of the NLRP3 inflammasome.

Table VI

Classical inhibitors of the NLRP3 inflammasome.

A, Indirect inhibitors
NameMechanism of action(Refs.)
AuranofinInhibition of the differentiation and maturation of NLRP3 and pro-IL-1β by inhibiting NF-ĸB activation.(207)
FC11A-2Inhibition of the expression of NLRP3, ASC, caspase-1 and pro-IL-1β.(207,208)
β-Hydroxybutyrate Celastrol GlyburideInhibition of activation of NLRP3 inflammatory corpuscles is achieved by inhibiting K+ channels.(207-211)
Epigallocatechin-3-gallateInhibition of the production of ROS in mitochondria, which is the upstream signal activated by NLRP3 inflammatory corpuscles, and inhibition of the synthesis of mitochondrial DNA.(207)
Licochalcone AInhibition of the upstream signal mitochondrial ROS production of NLRP3 inflammatory corpuscle activation.(207)

B, Direct inhibitors

NameMechanism of action(Refs.)

Provitamin ADirect binding to the PYD structure of NLRP3 to inhibit the activation of NLRP3 inflammatory bodies.(212)
CY-09Inhibition of ATPase activity of NLRP3.(213)
MNSDirect binding to LRR and NACHT domains of NLRP3 and subsequent inhibition of ATPase activity of NLRP3.(214)
Bay11-7082Alkylation modification of the ATPase active region of NLRP3 can be carried out and NF-ĸB signaling can be inhibited.(215,216)

C, Protein inhibitors of other components of NLRP3 inflammasome

NameMechanism of action(Refs.)
ASC inhibitor CAPEDirect binding of ASC and blocking of the interaction between NLRP3 and ASC.(217)
Caspase-1 inhibitor VX-740The activity of caspase-1 is inhibited by covalent modification of a cysteine residue at the active site of caspase-1.(218)
IL-1β inhibitors
 AnakinraAntagonist of IL-1β receptor.(219)
 CankinumabIL-1β-neutralizing antibody.(219)
 RilonaceptAn IL-1 trapping agent, which connects two molecules of IL-1β receptors with an immunoglobulin Fc segment.(219)

[i] NLRP3, Nod-like receptor family pyrin domain containing 3; ROS, reactive oxygen species; CAPE, caffeic acid phenethyl ester; ASC, Apoptosis associated spot-like protein.

Indirect inhibitors

Indirect inhibitors mainly inhibit the activation of NLRP3 inflammasome in three ways: Inhibiting the protein expression of NLRP3 inflammasome, blocking the upstream signaling pathway of the NLRP3 inflammasome and inhibiting the post-translational modification of regulatory proteins of NLRP3. For instance, auranofin inhibits the differentiation and maturation of NLRP3 and pro-IL-1β by inhibiting NF-ĸB activation, and inhibitors such as FC11A-2 inhibit the expression of NLRP3, ASC, caspase-1 and pro-IL-1β. β-Hydroxybutyrate, celastrol and glyburide inhibit the activation of NLRP3 inflammasome by inhibiting K+ channels. Epigallocatechin-3-gallate (EGCG) and Licochalcone A inhibit the production of ROS in the upstream signaling of NLRP3 inflammasome activation, and EGCG can also inhibit mitochondrial DNA synthesis (207-211). These indirect inhibitors have been proven to have significant therapeutic effects in specific NLRP3 inflammasome-related disease models in previous studies, but the defects are also obvious: i) The mechanism of most indirect inhibitors is unclear; ii) the signaling pathways inhibited by numerous inhibitors lack specificity, and these signaling pathways may not be unique to NLRP3 inflammasome, which may easily lead to immunosuppression and even infection; iii) the upstream signaling pathway network of the NLRP3 inflammasome is complex and it is difficult to effectively inhibit the activation process of NLRP3 inflammasome only by inhibiting one of the signaling processes; iv) this type of inhibitor is only in the experimental stage of disease models and has not been applied in the clinic.

Direct inhibitors

Direct inhibitors of NLRP3 inflammasome have the advantages of clear mechanisms of action and specific inhibition of NLRP3 inflammasome activation. For instance, in the study of GA, Yang et al (212) found that provitamin A can directly combine with the PYD structure of NLRP3, inhibit the activation of NLRP3 inflammasome and directly reduce the expression level of IL-1β secreted by synovial cells isolated from patients with GA. CY-09 also inhibits the ATPase activity of NLRP3, which has also been proven to have the effect of alleviating GA in mice (213). There are many such direct inhibitors. For instance, 3,4-meth ylenedioxy-β-nitrostyrene can directly bind to the LRR and NACHT domains of NLRP3 and then inhibit the activation of the NLRP3 inflammasome by inhibiting the ATPase activity of NLRP3 (214). Bay11-7082 can alkylate the ATPase active region of NLRP3, inhibit the NF-ĸB signal and further inhibit the activation of NLRP3 inflammasome (215,216). Although direct inhibitors of NLRP3 have obvious advantages and show good therapeutic potential, and many inhibitors directly targeting NLRP3 protein have been identified, there are still no therapeutic drugs that specifically target NLRP3 inflammasome in the clinic. Although a few inhibitors have been promoted to clinical trials of inflammatory diseases related to NLRP3, their clinical efficacy and safety still need to be further verified, which is still a long time from their potential clinical application.

Protein inhibitors of other components of NLRP3 inflammasome

Protein inhibitors of other components of NLRP3 inflammasome include ASC inhibitors, caspase-1 inhibitors and IL-1β/IL-18 inhibitors. Caffeine acid phenethyl ester (CAPE) is the only reported ASC inhibitor at present. CAPE binds directly to ASC and then inhibits the activation of NLRP3 inflammasome by blocking the interaction between NLRP3 and ASC (217). VX-740 is a typical inhibitor of caspase-1, which impairs the activity of caspase-1 by covalently modifying the cysteine residue at the active site of caspase-1, thus inhibiting the activation of the NLRP3 inflammasome, and has shown good anti-inflammatory effects in the first and second clinical trials for patients with RA. However, both ASC and caspase-1 are component proteins needed for the activation of other inflammatory corpuscles, and the lack of specificity may lead to immunosuppression, which will eventually increase the risk of infection (218). IL-1β inhibitor is the only strategy that can be used to treat NLRP3 inflammasome-related diseases. Its three related biological agents, anakinra, IL-1β-neutralizing antibody cankinumab and soluble inducible receptor rilonacept, have been approved by the Food and Drug Administration, and previous studies have confirmed that it can effectively reduce the inflammatory response of joint, bone and muscle diseases, hereditary systemic autoinflammatory diseases and systemic and local inflammatory diseases (219). The treatment with IL-18 antagonist is similar to that with IL-1β antagonist, but it has not been used in clinical treatment. Although anti-IL-1β therapy has been proven to be applicable in the clinic, the related side effects are quite serious: i) IL-1β is not the specific downstream pathway of NLRP3 inflammatory corpuscles and other cytokines such as IL-18 may be involved in the occurrence and development of inflammatory diseases. ii) IL-1β can be produced by other inflammatory corpuscles or independent of inflammatory corpuscles. Blocking IL-1β signaling may increase the risk of infection. Studies have confirmed that certain infections are even fatal. iii) The curently available biological agents targeting IL-1β have a weak ability to penetrate the blood-brain barrier, which leads to the related treatment methods possibly not being suitable for central nervous system diseases (220). In short, simply blocking inflammatory cytokine signals may not be an effective or specific treatment.

Research on targeted gene therapy

Most inhibitors only inhibit the upstream signaling of the NLRP3 inflammasome, but not NLRP3 itself, which limits the effectiveness of inhibitors and may lead to unexpected side effects. Therefore, gene editing is probably an effective measure for NLRP3 and numerous scientists have performed large amounts of research on it.

Role of miRNA in the regulation of NLRP3 inflammasome

Studies have proved that miRNAs regulate inflammatory corpuscles after transcription. They can inhibit or increase the expression of inflammatory genes by binding to their mRNA targets. In the literature, it is known that different miRNAs regulate different inflammatory corpuscles and NLRP3 is one of the star members (Table VII).

Table VII

List of miRNAs known to target NLRP3 inflammasome genes and associated diseases.

Table VII

List of miRNAs known to target NLRP3 inflammasome genes and associated diseases.

miRNATarget geneDisease(Refs.)
miR-223NLRP3Inflammatory bowel diseases, respiratory diseases and hepatocellular carcinoma(221-223)
miR-133aNLRP3Inflammatory diseases(224)
miR-22NLRP3Gastric cancer(225)
miR-30eNLRP3PD(226)
miR-7NLRP3PD(227)
miR-146a-5pNLRP3MS(228)
miR-20b-5pNLRP3MS(229)
miR-495-3pNLRP3Cardiovascular disease(230)

[i] miRNA/miR, microRNA; NLRP3, Nod-like receptor family pyrin domain containing 3; PD, Parkinson's disease; MS, multiple sclerosis.

MiR-233-3p is the first human miRNA that has been proven to regulate NLRP3. Related studies found that NLRP3 contained the conserved binding site of miR-223-3p in its 3′-UTR. The binding between this conserved region and miR-223-3p leads to decreased NLRP3 activity and mutation of this region leads to the complete loss of apoptosis regulation mediated by miR-223 (221-223). In the process of studying the role of miRNA in NLRP3 inflammasome, Bandyopadhyay et al (224) overexpressed and inhibited miR-133a-1 in differentiated THP1 cells and found that overexpression of miR-133a-1 increased the levels of caspase-1 and IL-1β. They demonstrated that miR-133a-1 did not change the basic expression of individual components of the NLRP3 complex but could regulate IL-1β (224). Other scholars identified the constitutive expression of miR-22 in gastric mucosa and found that miR-22 directly targeted NLRP3 at the transcription level, which weakened the carcinogenic effect of NLRP3 in vitro and in vivo. As mentioned above, NLRP3 inflammatory corpuscles play an important role in the process of Hp infection, and Hp infection significantly inhibits the expression of miR-22, which directly inhibits the biological effect of miR-22, leading to the activation of NLRP3 inflammatory corpuscles, thus promoting cell proliferation, aggravating the course of disease and even leading to the transformation into gastric cancer (225).

Other miRNAs can affect the NLRP3 inflammasome. For instance, Li et al (226) found that NLRP3 showed a conserved binding site for miR-30e in its 3′-UTR, indicating that there is a connection between miR-30e and neuroinflammation mediated by NLRP3 inflammatory corpuscles in the pathogenesis of PD. Animal experiments have confirmed that in the induced PD mouse model, miR-30e can improve neuronal damage by negatively regulating the expression of NLRP3 and inhibiting the activation of NLRP3 inflammatory bodies (226). MiR-7 and neuroinflammation mediated by the NLRP3 inflammasome are also directly related to the pathogenesis of PD, which directly regulates the expression of α-Synuclein in dopaminergic neurons through post-transcriptional regulation, which is related to the pathophysiology of PD (227). During the research of multiple sclerosis, Boxberger et al (228) and Tezcan et al (229) also found that miR-146a-5p and miR-20b-5p can also target and regulate NLRP3 inflammasome to control the progress of the disease. MiR-495-3p may regulate the progression of cardiovascular diseases by targeting NLRP3 (230).

Gene editing targeting NLRP3 inflammasome

As the third-generation genome editing tool, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas 9) can specifically and effectively destroy or repair pathogenic genes through a single guide (g)RNA-directed Cas 9 nuclease. To date, T cells modified by CRISPR/Cas 9 in vitro have entered the clinical trials stage for the treatment of metastatic non-small cell lung cancer (231). Adenovirus-associated or adeno-associated virus-mediated CRISPR/Cas9 delivery has been used to treat diseases such as hypercholesterolemia and Duchenne muscular dystrophy (232,233). Jiang et al (213) used CRISPR/Cas9 to directly destroy the key molecule NLRP3 at the genomic level and the results showed that it completely inhibits the activation of NLRP3 while avoiding the potential risk of inhibiting the off-target pathway of anti-inflammatory biological agents and inhibitors. In a mouse model experiment, Xu et al (234) encapsulated mCas9 and gNLRP3 in cationic lipid-assisted nanoparticle (CLAN) and then delivered Cas9 mRNA (mCas9)/gNLRP3 to macrophages, which prevented septic shock and peritonitis, and improved diabetes-related inflammation and insulin resistance by destroying NLRP3 in macrophages. To date, only a small number of studies on gene editing of NLRP3 have been published, but scholars have successfully verified that CLAN carrying mCas9/gNLRP3 can alleviate acute and chronic inflammatory diseases, which is undoubtedly expected to be a potential treatment for NLRP3-dependent inflammatory diseases.

Discussion

With the development of research on the structure and function of the NLRP3 inflammasome, more and more evidence shows that the NLRP3 inflammasome is a key molecule mediating tissue damage in numerous systemic diseases, and their pro-inflammatory factor release and cell death effects can aggravate the corresponding tissue damage. As mentioned above, NLRP3 plays an important role in common diseases of the respiratory system, cardiovascular system, digestive system, bone joint system and central nervous system. The NLRP3/caspase-1/IL-1β/IL-18 axis is a good target for treating these diseases.

Small molecular inhibitors against NLRP3 inflammasome have shown certain therapeutic prospects. Among the known indirect inhibitors, direct inhibitors and other protein inhibitors of NLRP3 inflammasome (ASC, caspase-1, IL-1β/IL-18), only IL-1β inhibitors can be used in clinical treatment and others are still in the experimental stage. In addition to specific small molecules, the effective components of classical drugs and plant extracts have also been verified to inhibit the activation of NLRP3 nonspecifically. Targeting NLRP3 through exosomes and miRNA or certain gene editing methods may also provide more ideas for related research.

However, research on NLRP3 inflammasome in the field of diseases is still in its infancy and the in-depth mechanism of activation and assembly of NLRP3 inflammasome and its mediation of cell death requires further clarification. The defects of various inhibitors, such as low specificity, likeliness to produce immunosuppression and possible infection, need further improvement. Therefore, the role of the NLRP3 inflammasome in the occurrence and development of numerous systemic inflammatory diseases has been confirmed. However, there is still a long way to go for its clinical treatment and transformation. Furthermore, although gene editing or non-coding RNA have successfully confirmed the feasibility of the new targeted therapy of NLRP3 in basic research, they are only of great significance for the diagnosis of diseases in clinical activities from the perspective of epigenetics and are still rare in clinical application. How to improve patients' symptoms and delay the progression of the disease as much as possible while ensuring biological safety requires further experimental models and clinical research to confirm. Further elucidation of the mechanisms of the NLRP3 inflammasome will lay the foundation for fully understanding the occurrence and development of related diseases and proposing specific targeted therapies with NLRP3 inflammasome inhibitors and NLRP3 gene intervention as the core.

It is worth noting that natural small molecular compounds of traditional Chinese medicine, such as polyphenols, flavonoids and alkaloids, have attracted the wide attention of scholars because of their rich sources, complex and diverse structures, high biocompatibility, few adverse reactions and incomparable biochemical valence diversity of synthetic compounds. Although the specific mechanism of action remains to be clarified, it has been preliminarily confirmed that dihydromyricetin (235) and amygdalin (236) can inhibit the NF-κB signaling pathway in the start-up stage; oxyphyllin (237) and piperine (238) can block the interaction between NEK7 and NLRP3; tanshinone I (239) can block the interaction between ASC and NLRP3; chrysotin (240) and silybin (241) can inhibit the activation of caspase-1. Related research is still in the early stage and more evidence is needed in the future to clarify the specific molecular mechanisms, as well as to evaluate the bioavailability, effectiveness and safety of the compounds, so as to determine whether they are suitable for treating related diseases and beneficial to improve clinical applications.

There have been numerous studies and summaries on the NLRP3 inflammasome and various systemic diseases in the past, but the relevant results are scattered and there is no systematic summary. There is still no comprehensive summary and analysis of the NLRP3 inflammasome and the whole clinical disease research. The role of NLRP3 in various systemic diseases is becoming increasingly significant. How to prepare related inhibitors or targeting methods with strong efficacy, long action time and high specificity has undoubtedly become the focus of current clinical research. In this paper, the diseases of various systems and the current treatment methods were comprehensively analyzed, so as to attract the attention of clinical workers in this field and provide a reference for follow-up researchers.

Availability of data and materials

Not applicable.

Authors' contributions

JL and NX designed the study; HW wrote the manuscript; WS and YL prepared the figures; and LM edited the manuscript. All authors have read and approved the manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Acknowledgments

Not applicable.

Funding

The study was supported by grants from the National Natural Science Foundation of China (grant nos. 81671563 and 82172486), Jiangsu Provincial Commission of Health and Family Planning, the 'Six One' Project of Jiangsu Province (grant no. LGY2016018) and the Jiangsu Provincial Personnel Department 'the Great of Six Talented Man Peak' Project (grant no. WSW-04).

References

1 

Li Y, Huang H, Liu B, Zhang Y, Pan X, Yu XY, Shen Z and Song YH: Inflammasomes as therapeutic targets in human diseases. Signal Transduct Target Ther. 6:2472021. View Article : Google Scholar : PubMed/NCBI

2 

Duncan JA, Bergstralh DT, Wang Y, Willingham SB, Ye Z, Zimmermann AG and Ting JP: Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling. Proc Natl Acad Sci USA. 104:8041–8046. 2007. View Article : Google Scholar : PubMed/NCBI

3 

Jo EK, Kim JK, Shin DM and Sasakawa C: Molecular mechanisms regulating NLRP3 inflammasome activation. Cell Mol Immunol. 13:148–159. 2016. View Article : Google Scholar :

4 

Swanson KV, Deng M and Ting JP: The NLRP3 inflammasome: Molecular activation and regulation to therapeutics. Nat Rev Immunol. 19:477–489. 2019. View Article : Google Scholar : PubMed/NCBI

5 

Ozaki E, Campbell M and Doyle SL: Targeting the NLRP3 inflammasome in chronic inflammatory diseases: Current perspectives. J Inflamm Res. 8:15–27. 2015.PubMed/NCBI

6 

Leemans JC, Cassel SL and Sutterwala FS: Sensing damage by the NLRP3 inflammasome. Immunol Rev. 243:152–162. 2011. View Article : Google Scholar : PubMed/NCBI

7 

Schroder K, Zhou R and Tschopp J: The NLRP3 inflammasome: A sensor for metabolic danger? Science. 327:296–300. 2010. View Article : Google Scholar : PubMed/NCBI

8 

Inoue M and Shinohara ML: NLRP3 Inflammasome and MS/EAE. Autoimmune Dis. 2013:8591452013.PubMed/NCBI

9 

Zhen Y and Zhang H: NLRP3 inflammasome and inflammatory bowel disease. Front Immunol. 10:2762019. View Article : Google Scholar : PubMed/NCBI

10 

Kelley N, Jeltema D, Duan Y and He Y: The NLRP3 inflammasome: An overview of mechanisms of activation and regulation. Int J Mol Sci. 20:33282019. View Article : Google Scholar : PubMed/NCBI

11 

Xu J and Núñez G: The NLRP3 inflammasome: Activation and regulation. Trends Biochem Sci. 48:331–344. 2023. View Article : Google Scholar

12 

Paik S, Kim JK, Silwal P, Sasakawa C and Jo EK: An update on the regulatory mechanisms of NLRP3 inflammasome activation. Cell Mol Immunol. 18:1141–1160. 2021. View Article : Google Scholar : PubMed/NCBI

13 

Muñoz-Planillo R, Kuffa P, Martínez-Colón G, Smith BL, Rajendiran TM and Núñez G: K+ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity. 38:1142–1153. 2013. View Article : Google Scholar

14 

Xu Z, Chen ZM, Wu X, Zhang L, Cao Y and Zhou P: Distinct molecular mechanisms underlying potassium efflux for NLRP3 inflammasome activation. Front Immunol. 11:6094412020. View Article : Google Scholar

15 

Groß CJ, Mishra R, Schneider KS, Médard G, Wettmarshausen J, Dittlein DC, Shi H, Gorka O, Koenig PA, Fromm S, et al: K(+) efflux-independent NLRP3 inflammasome activation by small molecules targeting mitochondria. Immunity. 45:761–773. 2016. View Article : Google Scholar

16 

Sanman LE, Qian Y, Eisele NA, Ng TM, van der Linden WA, Monack DM, Weerapana E and Bogyo M: Disruption of glycolytic flux is a signal for inflammasome signaling and pyroptotic cell death. Elife. 5:e136632016. View Article : Google Scholar : PubMed/NCBI

17 

Rajamäki K, Nordström T, Nurmi K, Åkerman KE, Kovanen PT, Öörni K and Eklund KK: Extracellular acidosis is a novel danger signal alerting innate immunity via the NLRP3 inflammasome. J Biol Chem. 288:13410–13419. 2013. View Article : Google Scholar : PubMed/NCBI

18 

Chae BJ, Lee KS, Hwang I and Yu JW: Extracellular acidification augments NLRP3-mediated inflammasome signaling in macrophages. Immune Netw. 23:e232023. View Article : Google Scholar : PubMed/NCBI

19 

Lee GS, Subramanian N, Kim AI, Aksentijevich I, Goldbach-Mansky R, Sacks DB, Germain RN, Kastner DL and Chae JJ: The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature. 492:123–127. 2012. View Article : Google Scholar : PubMed/NCBI

20 

Brough D, Le Feuvre RA, Wheeler RD, Solovyova N, Hilfiker S, Rothwell NJ and Verkhratsky A: Ca2+ stores and Ca2+ entry differentially contribute to the release of IL-1 beta and IL-1 alpha from murine macrophages. J Immunol. 170:3029–3036. 2003. View Article : Google Scholar : PubMed/NCBI

21 

Feldmeyer L, Keller M, Niklaus G, Hohl D, Werner S and Beer HD: The inflammasome mediates UVB-induced activation and secretion of interleukin-1beta by keratinocytes. Curr Biol. 17:1140–1145. 2007. View Article : Google Scholar : PubMed/NCBI

22 

Chu J, Thomas LM, Watkins SC, Franchi L, Núñez G and Salter RD: Cholesterol-dependent cytolysins induce rapid release of mature IL-1beta from murine macrophages in a NLRP3 inflammasome and cathepsin B-dependent manner. J Leukoc Biol. 86:1227–1238. 2009. View Article : Google Scholar : PubMed/NCBI

23 

Katsnelson MA, Rucker LG, Russo HM and Dubyak GR: K+ efflux agonists induce NLRP3 inflammasome activation independently of Ca2+ signaling. J Immunol. 194:3937–3952. 2015. View Article : Google Scholar : PubMed/NCBI

24 

Tang T, Lang X, Xu C, Wang X, Gong T, Yang Y, Cui J, Bai L, Wang J, Jiang W and Zhou R: CLICs-dependent chloride efflux is an essential and proximal upstream event for NLRP3 inflammasome activation. Nat Commun. 8:2022017. View Article : Google Scholar : PubMed/NCBI

25 

Verhoef PA, Kertesy SB, Lundberg K, Kahlenberg JM and Dubyak GR: Inhibitory effects of chloride on the activation of caspase-1, IL-1beta secretion, and cytolysis by the P2X7 receptor. J Immunol. 175:7623–7634. 2005. View Article : Google Scholar : PubMed/NCBI

26 

Mayes-Hopfinger L, Enache A, Xie J, Huang CL, Köchl R, Tybulewicz VLJ, Fernandes-Alnemri T and Alnemri ES: Chloride sensing by WNK1 regulates NLRP3 inflammasome activation and pyroptosis. Nat Commun. 12:45462021. View Article : Google Scholar : PubMed/NCBI

27 

Green JP, Yu S, Martín-Sánchez F, Pelegrin P, Lopez-Castejon G, Lawrence CB and Brough D: Chloride regulates dynamic NLRP3-dependent ASC oligomerization and inflammasome priming. Proc Natl Acad Sci USA. 115:E9371–E9380. 2018. View Article : Google Scholar : PubMed/NCBI

28 

Zhou R, Yazdi AS, Menu P and Tschopp J: A role for mitochondria in NLRP3 inflammasome activation. Nature. 469:221–225. 2011. View Article : Google Scholar

29 

Dominic A, Le NT and Takahashi M: Loop between NLRP3 inflammasome and reactive oxygen species. Antioxid Redox Signal. 36:784–796. 2022. View Article : Google Scholar

30 

Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N, Chen S, Ramanujan VK, Wolf AJ, Vergnes L, Ojcius DM, et al: Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 36:401–414. 2012. View Article : Google Scholar : PubMed/NCBI

31 

Iyer SS, He Q, Janczy JR, Elliott EI, Zhong Z, Olivier AK, Sadler JJ, Knepper-Adrian V, Han R, Qiao L, et al: Mitochondrial cardiolipin is required for Nlrp3 inflammasome activation. Immunity. 39:311–323. 2013. View Article : Google Scholar : PubMed/NCBI

32 

Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, Fitzgerald KA, Latz E, Moore KJ and Golenbock DT: The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol. 9:857–865. 2008. View Article : Google Scholar : PubMed/NCBI

33 

Lima H Jr, Jacobson LS, Goldberg MF, Chandran K, Diaz-Griffero F, Lisanti MP and Brojatsch J: Role of lysosome rupture in controlling Nlrp3 signaling and necrotic cell death. Cell Cycle. 12:1868–1878. 2013. View Article : Google Scholar : PubMed/NCBI

34 

Schorn C, Frey B, Lauber K, Janko C, Strysio M, Keppeler H, Gaipl US, Voll RE, Springer E, Munoz LE, et al: Sodium overload and water influx activate the NALP3 inflammasome. J Biol Chem. 286:35–41. 2011. View Article : Google Scholar :

35 

Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, Fitzgerald KA and Latz E: Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol. 9:847–856. 2008. View Article : Google Scholar : PubMed/NCBI

36 

Dostert C, Guarda G, Romero JF, Menu P, Gross O, Tardivel A, Suva ML, Stehle JC, Kopf M, Stamenkovic I, et al: Malarial hemozoin is a Nalp3 inflammasome activating danger signal. PLoS One. 4:e65102009. View Article : Google Scholar : PubMed/NCBI

37 

Orlowski GM, Colbert JD, Sharma S, Bogyo M, Robertson SA and Rock KL: Multiple cathepsins promote Pro-IL-1β synthesis and NLRP3-mediated IL-1β activation. J Immunol. 195:1685–1697. 2015. View Article : Google Scholar : PubMed/NCBI

38 

Kayagaki N, Stowe IB, Lee BL, O'Rourke K, Anderson K, Warming S, Cuellar T, Haley B, Roose-Girma M, Phung QT, et al: Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature. 526:666–671. 2015. View Article : Google Scholar : PubMed/NCBI

39 

Kayagaki N, Warming S, Lamkanfi M, Vande Walle L, Louie S, Dong J, Newton K, Qu Y, Liu J, Heldens S, et al: Non-canonical inflammasome activation targets caspase-11. Nature. 479:117–121. 2011. View Article : Google Scholar : PubMed/NCBI

40 

Shi J, Zhao Y, Wang Y, Gao W, Ding J, Li P, Hu L and Shao F: Inflammatory caspases are innate immune receptors for intracellular LPS. Nature. 514:187–192. 2014. View Article : Google Scholar : PubMed/NCBI

41 

Ding J, Wang K, Liu W, She Y, Sun Q, Shi J, Sun H, Wang DC and Shao F: Pore-forming activity and structural autoinhibition of the gasdermin family. Nature. 535:111–116. 2016. View Article : Google Scholar : PubMed/NCBI

42 

Ramirez MLG, Poreba M, Snipas SJ, Groborz K, Drag M and Salvesen GS: Extensive peptide and natural protein substrate screens reveal that mouse caspase-11 has much narrower substrate specificity than caspase-1. J Biol Chem. 293:7058–7067. 2018. View Article : Google Scholar : PubMed/NCBI

43 

Gaidt MM, Ebert TS, Chauhan D, Schmidt T, Schmid-Burgk JL, Rapino F, Robertson AA, Cooper MA, Graf T and Hornung V: Human monocytes engage an alternative inflammasome pathway. Immunity. 44:833–846. 2016. View Article : Google Scholar : PubMed/NCBI

44 

Wang L and Hauenstein AV: The NLRP3 inflammasome: Mechanism of action, role in disease and therapies. Mol Aspects Med. 76:1008892020. View Article : Google Scholar : PubMed/NCBI

45 

He Y, Franchi L and Núñez G: TLR agonists stimulate Nlrp3-dependent IL-1β production independently of the purinergic P2X7 receptor in dendritic cells and in vivo. J Immunol. 190:334–339. 2013. View Article : Google Scholar

46 

Wang C, Zhou J, Wang J, Li S, Fukunaga A, Yodoi J and Tian H: Progress in the mechanism and targeted drug therapy for COPD. Signal Transduct Target Ther. 5:2482020. View Article : Google Scholar : PubMed/NCBI

47 

Birrell MA and Eltom S: The role of the NLRP3 inflammasome in the pathogenesis of airway disease. Pharmacol Ther. 130:364–370. 2011. View Article : Google Scholar : PubMed/NCBI

48 

Cicko S, Lucattelli M, Müller T, Lommatzsch M, De Cunto G, Cardini S, Sundas W, Grimm M, Zeiser R, Dürk T, et al: Purinergic receptor inhibition prevents the development of smoke-induced lung injury and emphysema. J Immunol. 185:688–697. 2010. View Article : Google Scholar : PubMed/NCBI

49 

De Nardo D, De Nardo CM and Latz E: New insights into mechanisms controlling the NLRP3 inflammasome and its role in lung disease. Am J Pathol. 184:42–54. 2014. View Article : Google Scholar :

50 

Hosseinian N, Cho Y, Lockey RF and Kolliputi N: The role of the NLRP3 inflammasome in pulmonary diseases. Ther Adv Respir Dis. 9:188–197. 2015. View Article : Google Scholar : PubMed/NCBI

51 

Pauwels NS, Bracke KR, Dupont LL, Van Pottelberge GR, Provoost S, Vanden Berghe T, Vandenabeele P, Lambrecht BN, Joos GF and Brusselle GG: Role of IL-1α and the Nlrp3/caspase-1/IL-1β axis in cigarette smoke-induced pulmonary inflammation and COPD. Eur Respir J. 38:1019–1028. 2011. View Article : Google Scholar : PubMed/NCBI

52 

Hoshino T, Kato S, Oka N, Imaoka H, Kinoshita T, Takei S, Kitasato Y, Kawayama T, Imaizumi T, Yamada K, et al: Pulmonary inflammation and emphysema: Role of the cytokines IL-18 and IL-13. Am J Respir Crit Care Med. 176:49–62. 2007. View Article : Google Scholar : PubMed/NCBI

53 

Churg A, Zhou S, Wang X, Wang R and Wright JL: The role of interleukin-1beta in murine cigarette smoke-induced emphysema and small airway remodeling. Am J Respir Cell Mol Biol. 40:482–490. 2009. View Article : Google Scholar

54 

Eltom S, Stevenson CS, Rastrick J, Dale N, Raemdonck K, Wong S, Catley MC, Belvisi MG and Birrell MA: P2X7 receptor and caspase 1 activation are central to airway inflammation observed after exposure to tobacco smoke. PLoS One. 6:e240972011. View Article : Google Scholar : PubMed/NCBI

55 

Xu S, Panettieri RA Jr and Jude J: Metabolomics in asthma: A platform for discovery. Mol Aspects Med. 85:1009902022. View Article : Google Scholar :

56 

Müller T, Vieira RP, Grimm M, Dürk T, Cicko S, Zeiser R, Jakob T, Martin SF, Blumenthal B, Sorichter S, et al: A potential role for P2X7R in allergic airway inflammation in mice and humans. Am J Respir Cell Mol Biol. 44:456–464. 2011. View Article : Google Scholar

57 

Yazdi AS, Guarda G, Riteau N, Drexler SK, Tardivel A, Couillin I and Tschopp J: Nanoparticles activate the NLR pyrin domain containing 3 (Nlrp3) inflammasome and cause pulmonary inflammation through release of IL-1α and IL-1β. Proc Natl Acad Sci USA. 107:19449–19454. 2010. View Article : Google Scholar

58 

Ather JL, Ckless K, Martin R, Foley KL, Suratt BT, Boyson JE, Fitzgerald KA, Flavell RA, Eisenbarth SC and Poynter ME: Serum amyloid A activates the NLRP3 inflammasome and promotes Th17 allergic asthma in mice. J Immunol. 187:64–73. 2011. View Article : Google Scholar : PubMed/NCBI

59 

Idzko M, Hammad H, van Nimwegen M, Kool M, Willart MA, Muskens F, Hoogsteden HC, Luttmann W, Ferrari D, Di Virgilio F, et al: Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells. Nat Med. 13:913–919. 2007. View Article : Google Scholar : PubMed/NCBI

60 

Nakae S, Komiyama Y, Yokoyama H, Nambu A, Umeda M, Iwase M, Homma I, Sudo K, Horai R, Asano M and Iwakura Y: IL-1 is required for allergen-specific Th2 cell activation and the development of airway hypersensitivity response. Int Immunol. 15:483–490. 2003. View Article : Google Scholar : PubMed/NCBI

61 

Wang CC, Fu CL, Yang YH, Lo YC, Wang LC, Chuang YH, Chang DM and Chiang BL: Adenovirus expressing interleukin-1 receptor antagonist alleviates allergic airway inflammation in a murine model of asthma. Gene Ther. 13:1414–1421. 2006. View Article : Google Scholar : PubMed/NCBI

62 

Harada M, Obara K, Hirota T, Yoshimoto T, Hitomi Y, Sakashita M, Doi S, Miyatake A, Fujita K, Enomoto T, et al: A functional polymorphism in IL-18 is associated with severity of bronchial asthma. Am J Respir Crit Care Med. 180:1048–1055. 2009. View Article : Google Scholar : PubMed/NCBI

63 

Luo W, Hu J, Xu W and Dong J: Distinct spatial and temporal roles for Th1, Th2, and Th17 cells in asthma. Front Immunol. 13:9740662022. View Article : Google Scholar : PubMed/NCBI

64 

Besnard AG, Guillou N, Tschopp J, Erard F, Couillin I, Iwakura Y, Quesniaux V, Ryffel B and Togbe D: NLRP3 inflammasome is required in murine asthma in the absence of aluminum adjuvant. Allergy. 66:1047–1057. 2011. View Article : Google Scholar : PubMed/NCBI

65 

Eisenbarth SC, Colegio OR, O'Connor W, Sutterwala FS and Flavell RA: Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature. 453:1122–1126. 2008. View Article : Google Scholar : PubMed/NCBI

66 

Demento SL, Eisenbarth SC, Foellmer HG, Platt C, Caplan MJ, Mark Saltzman W, Mellman I, Ledizet M, Fikrig E, Flavell RA and Fahmy TM: Inflammasome-activating nanoparticles as modular systems for optimizing vaccine efficacy. Vaccine. 27:3013–3021. 2009. View Article : Google Scholar : PubMed/NCBI

67 

Sawada M, Kawayama T, Imaoka H, Sakazaki Y, Oda H, Takenaka S, Kaku Y, Azuma K, Tajiri M, Edakuni N, et al: IL-18 induces airway hyperresponsiveness and pulmonary inflammation via CD4+ T cell and IL-13. PLoS One. 8:e546232013. View Article : Google Scholar : PubMed/NCBI

68 

Yamagata S, Tomita K, Sato R, Niwa A, Higashino H and Tohda Y: Interleukin-18-deficient mice exhibit diminished chronic inflammation and airway remodelling in ovalbumin-induced asthma model. Clin Exp Immunol. 154:295–304. 2008. View Article : Google Scholar : PubMed/NCBI

69 

Allen IC, Jania CM, Wilson JE, Tekeppe EM, Hua X, Brickey WJ, Kwan M, Koller BH, Tilley SL and Ting JP: Analysis of NLRP3 in the development of allergic airway disease in mice. J Immunol. 188:2884–2893. 2012. View Article : Google Scholar : PubMed/NCBI

70 

Hartwig C, Tschernig T, Mazzega M, Braun A and Neumann D: Endogenous IL-18 in experimentally induced asthma affects cytokine serum levels but is irrelevant for clinical symptoms. Cytokine. 42:298–305. 2008. View Article : Google Scholar : PubMed/NCBI

71 

Leung CC, Yu IT and Chen W: Silicosis. Lancet. 379:2008–2018. 2012. View Article : Google Scholar : PubMed/NCBI

72 

Cassel SL, Eisenbarth SC, Iyer SS, Sadler JJ, Colegio OR, Tephly LA, Carter AB, Rothman PB, Flavell RA and Sutterwala FS: The Nalp3 inflammasome is essential for the development of silicosis. Proc Natl Acad Sci USA. 105:9035–9040. 2008. View Article : Google Scholar : PubMed/NCBI

73 

Jessop F, Hamilton RF, Rhoderick JF, Shaw PK and Holian A: Autophagy deficiency in macrophages enhances NLRP3 inflammasome activity and chronic lung disease following silica exposure. Toxicol Appl Pharmacol. 309:101–110. 2016. View Article : Google Scholar : PubMed/NCBI

74 

Tong SY, Davis JS, Eichenberger E, Holland TL and Fowler VG Jr: Staphylococcus aureus infections: Epidemiology, pathophysiology, clinical manifestations, and management. Clin Microbiol Rev. 28:603–661. 2015. View Article : Google Scholar : PubMed/NCBI

75 

Craven RR, Gao X, Allen IC, Gris D, Bubeck Wardenburg J, McElvania-Tekippe E, Ting JP and Duncan JA: Staphylococcus aureus alpha-hemolysin activates the NLRP3 inflammasome in human and mouse monocytic cells. PLoS One. 4:e74462009. View Article : Google Scholar

76 

Kebaier C, Chamberland RR, Allen IC, Gao X, Broglie PM, Hall JD, Jania C, Doerschuk CM, Tilley SL and Duncan JA: Staphylococcus aureus α-hemolysin mediates virulence in a murine model of severe pneumonia through activation of the NLRP3 inflammasome. J Infect Dis. 205:807–817. 2012. View Article : Google Scholar : PubMed/NCBI

77 

Bewley MA, Naughton M, Preston J, Mitchell A, Holmes A, Marriott HM, Read RC, Mitchell TJ, Whyte MK and Dockrell DH: Pneumolysin activates macrophage lysosomal membrane permeabilization and executes apoptosis by distinct mechanisms without membrane pore formation. mBio. 5:e01710–14. 2014. View Article : Google Scholar : PubMed/NCBI

78 

Witzenrath M, Pache F, Lorenz D, Koppe U, Gutbier B, Tabeling C, Reppe K, Meixenberger K, Dorhoi A, Ma J, et al: The NLRP3 inflammasome is differentially activated by pneumolysin variants and contributes to host defense in pneumococcal pneumonia. J Immunol. 187:434–440. 2011. View Article : Google Scholar : PubMed/NCBI

79 

McNeela EA, Burke A, Neill DR, Baxter C, Fernandes VE, Ferreira D, Smeaton S, El-Rachkidy R, McLoughlin RM, Mori A, et al: Pneumolysin activates the NLRP3 inflammasome and promotes proinflammatory cytokines independently of TLR4. PLoS Pathog. 6:e10011912010. View Article : Google Scholar : PubMed/NCBI

80 

van Lieshout MH, Scicluna BP, Florquin S and van der Poll T: NLRP3 and ASC differentially affect the lung transcriptome during pneumococcal pneumonia. Am J Respir Cell Mol Biol. 50:699–712. 2014. View Article : Google Scholar

81 

Gravina AG, Zagari RM, De Musis C, Romano L, Loguercio C and Romano M: Helicobacter pylori and extragastric diseases: A review. World J Gastroenterol. 24:3204–3221. 2018. View Article : Google Scholar : PubMed/NCBI

82 

Venerito M, Vasapolli R, Rokkas T, Delchier JC and Malfertheiner P: Helicobacter pylori, gastric cancer and other gastrointestinal malignancies. Helicobacter. 22(Suppl 1)John Wiley and Sons; 2017, View Article : Google Scholar

83 

Pachathundikandi SK, Blaser N, Bruns H and Backert S: Helicobacter pylori avoids the critical activation of NLRP3 inflammasome-mediated production of oncogenic mature IL-1β in human immune cells. Cancers (Basel). 12:8032020. View Article : Google Scholar

84 

Li X, Liu S, Luo J, Liu A, Tang S, Liu S, Yu M and Zhang Y: Helicobacter pylori induces IL-1β and IL-18 production in human monocytic cell line through activation of NLRP3 inflammasome via ROS signaling pathway. Pathog Dis. 73:ftu0242015. View Article : Google Scholar

85 

Shigematsu Y, Niwa T, Rehnberg E, Toyoda T, Yoshida S, Mori A, Wakabayashi M, Iwakura Y, Ichinose M, Kim YJ and Ushijima T: Interleukin-1β induced by Helicobacter pylori infection enhances mouse gastric carcinogenesis. Cancer Lett. 340:141–147. 2013. View Article : Google Scholar : PubMed/NCBI

86 

Serizawa T, Hirata Y, Hayakawa Y, Suzuki N, Sakitani K, Hikiba Y, Ihara S, Kinoshita H, Nakagawa H, Tateishi K and Koike K: Gastric metaplasia induced by helicobacter pylori is associated with enhanced SOX9 expression via interleukin-1 signaling. Infect Immun. 84:562–572. 2015. View Article : Google Scholar : PubMed/NCBI

87 

Kameoka S, Kameyama T, Hayashi T, Sato S, Ohnishi N, Hayashi T, Murata-Kamiya N, Higashi H, Hatakeyama M and Takaoka A: Helicobacter pylori induces IL-1β protein through the inflammasome activation in differentiated macrophagic cells. Biomed Res. 37:21–27. 2016. View Article : Google Scholar

88 

Yu Q, Shi H, Ding Z, Wang Z, Yao H and Lin R: The E3 ubiquitin ligase TRIM31 attenuates NLRP3 inflammasome activation in Helicobacter pylori-associated gastritis by regulating ROS and autophagy. Cell Commun Signal. 21:12023. View Article : Google Scholar : PubMed/NCBI

89 

Davari F, Shokri-Shirvani J, Sepidarkish M and Nouri HR: Elevated expression of the AIM2 gene in response to Helicobacter pylori along with the decrease of NLRC4 inflammasome is associated with peptic ulcer development. APMIS. 131:339–350. 2023. View Article : Google Scholar : PubMed/NCBI

90 

Asrani SK, Devarbhavi H, Eaton J and Kamath PS: Burden of liver diseases in the world. J Hepatol. 70:151–171. 2019. View Article : Google Scholar

91 

Sharma A and Nagalli S: Chronic Liver Disease. StatPearls [Internet] Treasure Island, FL: 2023

92 

Wree A, McGeough MD, Peña CA, Schlattjan M, Li H, Inzaugarat ME, Messer K, Canbay A, Hoffman HM and Feldstein AE: NLRP3 inflammasome activation is required for fibrosis development in NAFLD. J Mol Med (Berl). 92:1069–1082. 2014. View Article : Google Scholar : PubMed/NCBI

93 

Arab JP, Arrese M and Trauner M: Recent insights into the pathogenesis of nonalcoholic fatty liver disease. Annu Rev Pathol. 13:321–350. 2018. View Article : Google Scholar : PubMed/NCBI

94 

Lee HM, Kim JJ, Kim HJ, Shong M, Ku BJ and Jo EK: Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes. 62:194–204. 2013. View Article : Google Scholar

95 

Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, Ravussin E, Stephens JM and Dixit VD: The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med. 17:179–188. 2011. View Article : Google Scholar : PubMed/NCBI

96 

Csak T, Ganz M, Pespisa J, Kodys K, Dolganiuc A and Szabo G: Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells. Hepatology. 54:133–144. 2011. View Article : Google Scholar : PubMed/NCBI

97 

Mellinger JL: Epidemiology of alcohol use and alcoholic liver disease. Clin Liver Dis (Hoboken). 13:136–139. 2019. View Article : Google Scholar : PubMed/NCBI

98 

Ohashi K, Pimienta M and Seki E: Alcoholic liver disease: A current molecular and clinical perspective. Liver Res. 2:161–172. 2018. View Article : Google Scholar

99 

Voican CS, Njiké-Nakseu M, Boujedidi H, Barri-Ova N, Bouchet-Delbos L, Agostini H, Maitre S, Prévot S, Cassard-Doulcier AM, Naveau S and Perlemuter G: Alcohol withdrawal alleviates adipose tissue inflammation in patients with alcoholic liver disease. Liver Int. 35:967–978. 2015. View Article : Google Scholar

100 

Petrasek J, Bala S, Csak T, Lippai D, Kodys K, Menashy V, Barrieau M, Min SY, Kurt-Jones EA and Szabo G: IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. J Clin Invest. 122:3476–3489. 2012. View Article : Google Scholar : PubMed/NCBI

101 

Dixon LJ, Berk M, Thapaliya S, Papouchado BG and Feldstein AE: Caspase-1-mediated regulation of fibrogenesis in diet-induced steatohepatitis. Lab Invest. 92:713–723. 2012. View Article : Google Scholar : PubMed/NCBI

102 

Bataller R and Brenner DA: Liver fibrosis. J Clin Invest. 115:209–218. 2005. View Article : Google Scholar : PubMed/NCBI

103 

Boaru SG, Borkham-Kamphorst E, Tihaa L, Haas U and Weiskirchen R: Expression analysis of inflammasomes in experimental models of inflammatory and fibrotic liver disease. J Inflamm (Lond). 9:492012. View Article : Google Scholar : PubMed/NCBI

104 

Alyaseer AAA, de Lima MHS and Braga TT: The role of NLRP3 inflammasome activation in the epithelial to mesenchymal transition process during the fibrosis. Front Immunol. 11:8832020. View Article : Google Scholar : PubMed/NCBI

105 

Lozano-Ruiz B, Bachiller V, García-Martínez I, Zapater P, Gómez-Hurtado I, Moratalla A, Giménez P, Bellot P, Francés R, Such J and González-Navajas JM: Absent in melanoma 2 triggers a heightened inflammasome response in ascitic fluid macrophages of patients with cirrhosis. J Hepatol. 62:64–71. 2015. View Article : Google Scholar

106 

Liu X, Zhou W, Zhang X, Lu P, Du Q, Tao L, Ding Y, Wang Y and Hu R: Dimethyl fumarate ameliorates dextran sulfate sodium-induced murine experimental colitis by activating Nrf2 and suppressing NLRP3 inflammasome activation. Biochem Pharmacol. 112:37–49. 2016. View Article : Google Scholar : PubMed/NCBI

107 

Sivakumar PV, Westrich GM, Kanaly S, Garka K, Born TL, Derry JM and Viney JL: Interleukin 18 is a primary mediator of the inflammation associated with dextran sulphate sodium induced colitis: Blocking interleukin 18 attenuates intestinal damage. Gut. 50:812–820. 2002. View Article : Google Scholar : PubMed/NCBI

108 

Siegmund B, Fantuzzi G, Rieder F, Gamboni-Robertson F, Lehr HA, Hartmann G, Dinarello CA, Endres S and Eigler A: Neutralization of interleukin-18 reduces severity in murine colitis and intestinal IFN-gamma and TNF-alpha production. Am J Physiol Regul Integr Comp Physiol. 281:R1264–R1273. 2001. View Article : Google Scholar : PubMed/NCBI

109 

Siegmund B: Interleukin-1beta converting enzyme (caspase-1) in intestinal inflammation. Biochem Pharmacol. 64:1–8. 2002. View Article : Google Scholar : PubMed/NCBI

110 

Zhao S, Gong Z, Zhou J, Tian C, Gao Y, Xu C, Chen Y, Cai W and Wu J: Deoxycholic acid triggers NLRP3 inflammasome activation and aggravates DSS-induced colitis in mice. Front Immunol. 7:5362016. View Article : Google Scholar : PubMed/NCBI

111 

Zherebiatiev A and Kamyshnyi A: Expression levels of proinflammatory cytokines and NLRP3 inflammasome in an experimental model of oxazolone-induced colitis. Iran J Allergy Asthma Immunol. 15:39–45. 2016.PubMed/NCBI

112 

Bauer C, Duewell P, Lehr HA, Endres S and Schnurr M: Protective and aggravating effects of Nlrp3 inflammasome activation in IBD models: Influence of genetic and environmental factors. Dig Dis. 30(Suppl 1): S82–S90. 2012. View Article : Google Scholar

113 

Allen IC, TeKippe EM, Woodford RM, Uronis JM, Holl EK, Rogers AB, Herfarth HH, Jobin C and Ting JP: The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J Exp Med. 207:1045–1056. 2010. View Article : Google Scholar : PubMed/NCBI

114 

Zaki MH, Boyd KL, Vogel P, Kastan MB, Lamkanfi M and Kanneganti TD: The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity. 32:379–391. 2010. View Article : Google Scholar : PubMed/NCBI

115 

Dupaul-Chicoine J, Yeretssian G, Doiron K, Bergstrom KS, McIntire CR, LeBlanc PM, Meunier C, Turbide C, Gros P, Beauchemin N, et al: Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases. Immunity. 32:367–378. 2010. View Article : Google Scholar : PubMed/NCBI

116 

Radtke F and Clevers H: Self-renewal and cancer of the gut: two sides of a coin. Science. 307:1904–1909. 2005. View Article : Google Scholar : PubMed/NCBI

117 

Itzkowitz SH and Yio X: Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: The role of inflammation. Am J Physiol Gastrointest Liver Physiol. 287:G7–G17. 2004. View Article : Google Scholar : PubMed/NCBI

118 

Du Q, Wang Q, Fan H, Wang J, Liu X, Wang H, Wang Y and Hu R: Dietary cholesterol promotes AOM-induced colorectal cancer through activating the NLRP3 inflammasome. Biochem Pharmacol. 105:42–54. 2016. View Article : Google Scholar : PubMed/NCBI

119 

Micallef MJ, Tanimoto T, Kohno K, Ikeda M and Kurimoto M: Interleukin 18 induces the sequential activation of natural killer cells and cytotoxic T lymphocytes to protect syngeneic mice from transplantation with Meth A sarcoma. Cancer Res. 57:4557–4563. 1997.PubMed/NCBI

120 

Micallef MJ, Yoshida K, Kawai S, Hanaya T, Kohno K, Arai S, Tanimoto T, Torigoe K, Fujii M, Ikeda M and Kurimoto M: In vivo antitumor effects of murine interferon-gamma-inducing factor/interleukin-18 in mice bearing syngeneic Meth A sarcoma malignant ascites. Cancer Immunol Immunother. 43:361–367. 1997. View Article : Google Scholar : PubMed/NCBI

121 

Osaki T, Péron JM, Cai Q, Okamura H, Robbins PD, Kurimoto M, Lotze MT and Tahara H: IFN-gamma-inducing factor/IL-18 administration mediates IFN-gamma- and IL-12-independent antitumor effects. J Immunol. 160:1742–1749. 1998. View Article : Google Scholar : PubMed/NCBI

122 

Coughlin CM, Salhany KE, Wysocka M, Aruga E, Kurzawa H, Chang AE, Hunter CA, Fox JC, Trinchieri G and Lee WM: Interleukin-12 and interleukin-18 synergistically induce murine tumor regression which involves inhibition of angiogenesis. J Clin Invest. 101:1441–1452. 1998. View Article : Google Scholar : PubMed/NCBI

123 

Hegardt P, Widegren B, Li L, Sjögren B, Kjellman C, Sur I and Sjögren HO: Nitric oxide synthase inhibitor and IL-18 enhance the anti-tumor immune response of rats carrying an intrahepatic colon carcinoma. Cancer Immunol Immunother. 50:491–501. 2001. View Article : Google Scholar

124 

Zaki MH, Vogel P, Body-Malapel M, Lamkanfi M and Kanneganti TD: IL-18 production downstream of the Nlrp3 inflammasome confers protection against colorectal tumor formation. J Immunol. 185:4912–4920. 2010. View Article : Google Scholar : PubMed/NCBI

125 

Reuter BK and Pizarro TT: Commentary: the role of the IL-18 system and other members of the IL-1R/TLR superfamily in innate mucosal immunity and the pathogenesis of inflammatory bowel disease: Friend or foe? Eur J Immunol. 34:2347–2355. 2004. View Article : Google Scholar : PubMed/NCBI

126 

Swaroop VS, Chari ST and Clain JE: Severe acute pancreatitis. JAMA. 291:2865–2868. 2004. View Article : Google Scholar : PubMed/NCBI

127 

Yang ZW, Meng XX and Xu P: Central role of neutrophil in the pathogenesis of severe acute pancreatitis. J Cell Mol Med. 19:2513–2520. 2015. View Article : Google Scholar : PubMed/NCBI

128 

Janiak A, Leśniowski B, Jasińska A, Pietruczuk M and Małecka-Panas E: Interleukin 18 as an early marker or prognostic factor in acute pancreatitis. Prz Gastroenterol. 10:203–207. 2015.

129 

Fu Q, Zhai Z, Wang Y, Xu L, Jia P, Xia P, Liu C, Zhang X, Qin T and Zhang H: NLRP3 deficiency alleviates severe acute pancreatitis and pancreatitis-associated lung injury in a mouse model. Biomed Res Int. 2018:12949512018. View Article : Google Scholar

130 

Hoque R, Farooq A, Ghani A, Gorelick F and Mehal WZ: Lactate reduces liver and pancreatic injury in Toll-like receptor- and inflammasome-mediated inflammation via GPR81-mediated suppression of innate immunity. Gastroenterology. 146:1763–1774. 2014. View Article : Google Scholar : PubMed/NCBI

131 

Wu BU, Hwang JQ, Gardner TH, Repas K, Delee R, Yu S, Smith B, Banks PA and Conwell DL: Lactated Ringer's solution reduces systemic inflammation compared with saline in patients with acute pancreatitis. Clin Gastroenterol Hepatol. 9:710–717.e1. 2011. View Article : Google Scholar : PubMed/NCBI

132 

Ren JD, Ma J, Hou J, Xiao WJ, Jin WH, Wu J and Fan KH: Hydrogen-rich saline inhibits NLRP3 inflammasome activation and attenuates experimental acute pancreatitis in mice. Mediators Inflamm. 2014:9308942014. View Article : Google Scholar : PubMed/NCBI

133 

Smolen JS, Aletaha D, Barton A, Burmester GR, Emery P, Firestein GS, Kavanaugh A, McInnes IB, Solomon DH, Strand V and Yamamoto K: Rheumatoid arthritis. Nat Rev Dis Primers. 4:180012018. View Article : Google Scholar : PubMed/NCBI

134 

Kolly L, Busso N, Palmer G, Talabot-Ayer D, Chobaz V and So A: Expression and function of the NALP3 inflammasome in rheumatoid synovium. Immunology. 129:178–185. 2010. View Article : Google Scholar :

135 

Rosengren S, Hoffman HM, Bugbee W and Boyle DL: Expression and regulation of cryopyrin and related proteins in rheumatoid arthritis synovium. Ann Rheum Dis. 64:708–714. 2005. View Article : Google Scholar

136 

Choulaki C, Papadaki G, Repa A, Kampouraki E, Kambas K, Ritis K, Bertsias G, Boumpas DT and Sidiropoulos P: Enhanced activity of NLRP3 inflammasome in peripheral blood cells of patients with active rheumatoid arthritis. Arthritis Res Ther. 17:2572015. View Article : Google Scholar : PubMed/NCBI

137 

Zhang Y, Zheng Y and Li H: NLRP3 Inflammasome plays an important role in the pathogenesis of collagen-induced arthritis. Mediators Inflamm. 2016:96562702016. View Article : Google Scholar : PubMed/NCBI

138 

Guo C, Fu R, Wang S, Huang Y, Li X, Zhou M, Zhao J and Yang N: NLRP3 inflammasome activation contributes to the pathogenesis of rheumatoid arthritis. Clin Exp Immunol. 194:231–243. 2018. View Article : Google Scholar : PubMed/NCBI

139 

Matmati M, Jacques P, Maelfait J, Verheugen E, Kool M, Sze M, Geboes L, Louagie E, Mc Guire C, Vereecke L, et al: A20 (TNFAIP3) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis. Nat Genet. 43:908–912. 2011. View Article : Google Scholar : PubMed/NCBI

140 

Vande Walle L, Van Opdenbosch N, Jacques P, Fossoul A, Verheugen E, Vogel P, Beyaert R, Elewaut D, Kanneganti TD, van Loo G and Lamkanfi M: Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis. Nature. 512:69–73. 2014. View Article : Google Scholar : PubMed/NCBI

141 

Li XF, Shen WW, Sun YY, Li WX, Sun ZH, Liu YH, Zhang L, Huang C, Meng XM and Li J: MicroRNA-20a negatively regulates expression of NLRP3 inflammasome by targeting TXNIP in adjuvant-induced arthritis fibroblast-like synoviocytes. Joint Bone Spine. 83:695–700. 2016. View Article : Google Scholar : PubMed/NCBI

142 

Huang Y, Lu D, Ma W, Liu J, Ning Q, Tang F and Li L: miR-223 in exosomes from bone marrow mesenchymal stem cells ameliorates rheumatoid arthritis via downregulation of NLRP3 expression in macrophages. Mol Immunol. 143:68–76. 2022. View Article : Google Scholar : PubMed/NCBI

143 

Li Y, Zheng JY, Liu JQ, Yang J, Liu Y, Wang C, Ma XN, Liu BL, Xin GZ and Liu LF: Succinate/NLRP3 inflammasome induces synovial fibroblast activation: Therapeutical effects of clematichinenoside AR on arthritis. Front Immunol. 7:5322016. View Article : Google Scholar : PubMed/NCBI

144 

Han X, Lin D, Huang W, Li D, Li N and Xie X: Mechanism of NLRP3 inflammasome intervention for synovitis in knee osteoarthritis: A review of TCM intervention. Front Genet. 14:11591672023. View Article : Google Scholar : PubMed/NCBI

145 

Derfus BA, Kurian JB, Butler JJ, Daft LJ, Carrera GF, Ryan LM and Rosenthal AK: The high prevalence of pathologic calcium crystals in pre-operative knees. J Rheumatol. 29:570–574. 2002.PubMed/NCBI

146 

Pazár B, Ea HK, Narayan S, Kolly L, Bagnoud N, Chobaz V, Roger T, Lioté F, So A and Busso N: Basic calcium phosphate crystals induce monocyte/macrophage IL-1β secretion through the NLRP3 inflammasome in vitro. J Immunol. 186:2495–2502. 2011. View Article : Google Scholar

147 

An S, Hu H, Li Y and Hu Y: Pyroptosis plays a role in osteoarthritis. Aging Dis. 11:1146–1157. 2020. View Article : Google Scholar : PubMed/NCBI

148 

Shao M, Lv D, Zhou K, Sun H and Wang Z: Senkyunolide A inhibits the progression of osteoarthritis by inhibiting the NLRP3 signalling pathway. Pharm Biol. 60:535–542. 2022. View Article : Google Scholar : PubMed/NCBI

149 

Lordén G, Sanjuán-García I, de Pablo N, Meana C, Alvarez-Miguel I, Pérez-García MT, Pelegrín P, Balsinde J and Balboa MA: Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptor activation. J Exp Med. 214:511–528. 2017. View Article : Google Scholar :

150 

Compston JE, McClung MR and Leslie WD: Osteoporosis. Lancet. 393:364–376. 2019. View Article : Google Scholar : PubMed/NCBI

151 

Alippe Y, Wang C, Ricci B, Xiao J, Qu C, Zou W, Novack DV, Abu-Amer Y, Civitelli R and Mbalaviele G: Bone matrix components activate the NLRP3 inflammasome and promote osteoclast differentiation. Sci Rep. 7:66302017. View Article : Google Scholar : PubMed/NCBI

152 

Detzen L, Cheat B, Besbes A, Hassan B, Marchi V, Baroukh B, Lesieur J, Sadoine J, Torrens C, Rochefort G, et al: NLRP3 is involved in long bone edification and the maturation of osteogenic cells. J Cell Physiol. 236:4455–4469. 2021. View Article : Google Scholar

153 

Jiang N, An J, Yang K, Liu J, Guan C, Ma C and Tang X: NLRP3 Inflammasome: A new target for prevention and control of osteoporosis? Front Endocrinol (Lausanne). 12:7525462021. View Article : Google Scholar : PubMed/NCBI

154 

Rocha FRG, Delitto AE, de Souza JAC, González-Maldonado LA, Wallet SM and Rossa Junior C: Relevance of caspase-1 and Nlrp3 inflammasome on inflammatory bone resorption in a murine model of periodontitis. Sci Rep. 10:78232020. View Article : Google Scholar : PubMed/NCBI

155 

Wang C, Xiao J, Nowak K, Gunasekera K, Alippe Y, Speckman S, Yang T, Kress D, Abu-Amer Y, Hottiger MO and Mbalaviele G: PARP1 hinders histone H2B occupancy at the NFATc1 promoter to restrain osteoclast differentiation. J Bone Miner Res. 35:776–788. 2020. View Article : Google Scholar

156 

Guaraná WL, Lima CAD, Barbosa AD, Crovella S and Sandrin-Garcia P: Can polymorphisms in NLRP3 inflammasome complex be associated with postmenopausal osteoporosis severity? Genes (Basel). 13:22712022. View Article : Google Scholar : PubMed/NCBI

157 

Xu L, Zhang L, Wang Z, Li C, Li S, Li L, Fan Q and Zheng L: Melatonin suppresses estrogen deficiency-induced osteoporosis and promotes osteoblastogenesis by inactivating the NLRP3 inflammasome. Calcif Tissue Int. 103:400–410. 2018. View Article : Google Scholar : PubMed/NCBI

158 

Dehlin M, Jacobsson L and Roddy E: Global epidemiology of gout: Prevalence, incidence, treatment patterns and risk factors. Nat Rev Rheumatol. 16:380–390. 2020. View Article : Google Scholar : PubMed/NCBI

159 

Mangan MSJ, Olhava EJ, Roush WR, Seidel HM, Glick GD and Latz E: Targeting the NLRP3 inflammasome in inflammatory diseases. Nat Rev Drug Discov. 17:6882018. View Article : Google Scholar : PubMed/NCBI

160 

Zhao Q, Xia N, Xu J, Wang Y, Feng L, Su D and Cheng Z: Pro-Inflammatory of PRDM1/SIRT2/NLRP3 axis in monosodium urate-induced acute gouty arthritis. J Innate Immun. 15:614–628. 2023. View Article : Google Scholar : PubMed/NCBI

161 

Renaudin F, Orliaguet L, Castelli F, Fenaille F, Prignon A, Alzaid F, Combes C, Delvaux A, Adimy Y, Cohen-Solal M, et al: Gout and pseudo-gout-related crystals promote GLUT1-mediated glycolysis that governs NLRP3 and interleukin-1β activation on macrophages. Ann Rheum Dis. 79:1506–1514. 2020. View Article : Google Scholar : PubMed/NCBI

162 

Lee HE, Yang G, Park YB, Kang HC, Cho YY, Lee HS and Lee JY: Epigallocatechin-3-gallate prevents acute gout by suppressing NLRP3 inflammasome activation and mitochondrial DNA synthesis. Molecules. 24:21382019. View Article : Google Scholar : PubMed/NCBI

163 

Li X, Liu Y, Luo C and Tao J: Z1456467176 alleviates gouty arthritis by allosterically modulating P2X7R to inhibit NLRP3 inflammasome activation. Front Pharmacol. 13:9799392022. View Article : Google Scholar : PubMed/NCBI

164 

Xin J, Wang Y, Zheng Z, Wang S, Na S and Zhang S: Treatment of intervertebral disc degeneration. Orthop Surg. 14:1271–1280. 2022. View Article : Google Scholar : PubMed/NCBI

165 

Chen F, Jiang G, Liu H, Li Z, Pei Y, Wang H, Pan H, Cui H, Long J, Wang J and Zheng Z: Melatonin alleviates intervertebral disc degeneration by disrupting the IL-1β/NF-κB-NLRP3 inflammasome positive feedback loop. Bone Res. 8:102020. View Article : Google Scholar

166 

Chen S, Wu X, Lai Y, Chen D, Bai X, Liu S, Wu Y, Chen M, Lai Y, Cao H, et al: Kindlin-2 inhibits Nlrp3 inflammasome activation in nucleus pulposus to maintain homeostasis of the intervertebral disc. Bone Res. 10:52022. View Article : Google Scholar : PubMed/NCBI

167 

Zhao K, An R, Xiang Q, Li G, Wang K, Song Y, Liao Z, Li S, Hua W, Feng X, et al: Acid-sensing ion channels regulate nucleus pulposus cell inflammation and pyroptosis via the NLRP3 inflammasome in intervertebral disc degeneration. Cell Prolif. 54:e129412021. View Article : Google Scholar

168 

Wojtasińska A, Frąk W, Lisińska W, Sapeda N, Młynarska E, Rysz J and Franczyk B: Novel insights into the molecular mechanisms of atherosclerosis. Int J Mol Sci. 24:134342023. View Article : Google Scholar

169 

Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nuñez G, Schnurr M, et al: NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 464:1357–1361. 2010. View Article : Google Scholar : PubMed/NCBI

170 

Paramel Varghese G, Folkersen L, Strawbridge RJ, Halvorsen B, Yndestad A, Ranheim T, Krohg-Sørensen K, Skjelland M, Espevik T, Aukrust P, et al: NLRP3 inflammasome expression and activation in human atherosclerosis. J Am Heart Assoc. 5:e0030312016. View Article : Google Scholar : PubMed/NCBI

171 

Usui F, Shirasuna K, Kimura H, Tatsumi K, Kawashima A, Karasawa T, Hida S, Sagara J, Taniguchi S and Takahashi M: Critical role of caspase-1 in vascular inflammation and development of atherosclerosis in Western diet-fed apolipoprotein E-deficient mice. Biochem Biophys Res Commun. 425:162–168. 2012. View Article : Google Scholar : PubMed/NCBI

172 

Zheng F, Xing S, Gong Z, Mu W and Xing Q: Silence of NLRP3 suppresses atherosclerosis and stabilizes plaques in apolipoprotein E-deficient mice. Mediators Inflamm. 2014:5072082014. View Article : Google Scholar : PubMed/NCBI

173 

Satoh M, Tabuchi T, Itoh T and Nakamura M: NLRP3 inflammasome activation in coronary artery disease: Results from prospective and randomized study of treatment with atorvastatin or rosuvastatin. Clin Sci (Lond). 126:233–241. 2014. View Article : Google Scholar

174 

Butts B, Gary RA, Dunbar SB and Butler J: The importance of NLRP3 inflammasome in heart failure. J Card Fail. 21:586–593. 2015. View Article : Google Scholar : PubMed/NCBI

175 

Bracey NA, Beck PL, Muruve DA, Hirota SA, Guo J, Jabagi H, Wright JR Jr, Macdonald JA, Lees-Miller JP, Roach D, et al: The Nlrp3 inflammasome promotes myocardial dysfunction in structural cardiomyopathy through interleukin-1β. Exp Physiol. 98:462–472. 2013. View Article : Google Scholar

176 

Mezzaroma E, Toldo S, Farkas D, Seropian IM, Van Tassell BW, Salloum FN, Kannan HR, Menna AC, Voelkel NF and Abbate A: The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse. Proc Natl Acad Sci USA. 108:19725–19730. 2011. View Article : Google Scholar : PubMed/NCBI

177 

Van Tassell BW, Seropian IM, Toldo S, Mezzaroma E and Abbate A: Interleukin-1β induces a reversible cardiomyopathy in the mouse. Inflamm Res. 62:637–640. 2013. View Article : Google Scholar : PubMed/NCBI

178 

Toldo S, Mezzaroma E, O'Brien L, Marchetti C, Seropian IM, Voelkel NF, Van Tassell BW, Dinarello CA and Abbate A: Interleukin-18 mediates interleukin-1-induced cardiac dysfunction. Am J Physiol Heart Circ Physiol. 306:H1025–H1031. 2014. View Article : Google Scholar : PubMed/NCBI

179 

Abbate A, Kontos MC, Grizzard JD, Biondi-Zoccai GG, Van Tassell BW, Robati R, Roach LM, Arena RA, Roberts CS, Varma A, et al: Interleukin-1 blockade with anakinra to prevent adverse cardiac remodeling after acute myocardial infarction (Virginia Commonwealth University Anakinra Remodeling Trial (VCU-ART) Pilot study). Am J Cardiol. 105:1371–1377.e1. 2010. View Article : Google Scholar

180 

Abbate A, Van Tassell BW, Biondi-Zoccai G, Kontos MC, Grizzard JD, Spillman DW, Oddi C, Roberts CS, Melchior RD, Mueller GH, et al: Effects of interleukin-1 blockade with anakinra on adverse cardiac remodeling and heart failure after acute myocardial infarction (from the Virginia Commonwealth University-Anakinra Remodeling Trial (2) (VCU-ART2) pilot study). Am J Cardiol. 111:1394–1400. 2013. View Article : Google Scholar : PubMed/NCBI

181 

Kawaguchi M, Takahashi M, Hata T, Kashima Y, Usui F, Morimoto H, Izawa A, Takahashi Y, Masumoto J, Koyama J, et al: Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation. 123:594–604. 2011. View Article : Google Scholar : PubMed/NCBI

182 

Sandanger Ø, Ranheim T, Vinge LE, Bliksøen M, Alfsnes K, Finsen AV, Dahl CP, Askevold ET, Florholmen G, Christensen G, et al: The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury. Cardiovasc Res. 99:164–174. 2013. View Article : Google Scholar : PubMed/NCBI

183 

Liu Y, Lian K, Zhang L, Wang R, Yi F, Gao C, Xin C, Zhu D, Li Y, Yan W, et al: TXNIP mediates NLRP3 inflammasome activation in cardiac microvascular endothelial cells as a novel mechanism in myocardial ischemia/reperfusion injury. Basic Res Cardiol. 109:4152014. View Article : Google Scholar : PubMed/NCBI

184 

Capizzi A, Woo J and Verduzco-Gutierrez M: Traumatic brain injury: An overview of epidemiology, pathophysiology, and medical management. Med Clin North Am. 104:213–238. 2020. View Article : Google Scholar : PubMed/NCBI

185 

Liu W, Chen Y, Meng J, Wu M, Bi F, Chang C, Li H and Zhang L: Ablation of caspase-1 protects against TBI-induced pyroptosis in vitro and in vivo. J Neuroinflammation. 15:482018. View Article : Google Scholar : PubMed/NCBI

186 

Xu X, Yin D, Ren H, Gao W, Li F, Sun D, Wu Y, Zhou S, Lyu L, Yang M, et al: Selective NLRP3 inflammasome inhibitor reduces neuroinflammation and improves long-term neurological outcomes in a murine model of traumatic brain injury. Neurobiol Dis. 117:15–27. 2018. View Article : Google Scholar : PubMed/NCBI

187 

Wallisch JS, Simon DW, Bayır H, Bell MJ, Kochanek PM and Clark RSB: Cerebrospinal fluid NLRP3 is increased after severe traumatic brain injury in infants and children. Neurocrit Care. 27:44–50. 2017. View Article : Google Scholar : PubMed/NCBI

188 

Geng F, Ma Y, Xing T, Zhuang X, Zhu J and Yao L: Effects of hyperbaric oxygen therapy on inflammasome signaling after traumatic brain injury. Neuroimmunomodulation. 23:122–129. 2016. View Article : Google Scholar : PubMed/NCBI

189 

Marino BLB, de Souza LR, Sousa KPA, Ferreira JV, Padilha EC, da Silva CHTP, Taft CA and Hage-Melim LIS: Parkinson's disease: A review from pathophysiology to treatment. Mini Rev Med Chem. 20:754–767. 2020. View Article : Google Scholar

190 

Marogianni C, Sokratous M, Dardiotis E, Hadjigeorgiou GM, Bogdanos D and Xiromerisiou G: Neurodegeneration and Inflammation-an interesting interplay in Parkinson's disease. Int J Mol Sci. 21:84212020. View Article : Google Scholar : PubMed/NCBI

191 

Mao Z, Liu C, Ji S, Yang Q, Ye H, Han H and Xue Z: The NLRP3 inflammasome is involved in the pathogenesis of Parkinson's disease in rats. Neurochem Res. 42:1104–1115. 2017. View Article : Google Scholar : PubMed/NCBI

192 

Qiao C, Zhang Q, Jiang Q, Zhang T, Chen M, Fan Y, Ding J, Lu M and Hu G: Inhibition of the hepatic Nlrp3 protects dopaminergic neurons via attenuating systemic inflammation in a MPTP/p mouse model of Parkinson's disease. J Neuroinflammation. 15:1932018. View Article : Google Scholar : PubMed/NCBI

193 

Villain N and Dubois B: Alzheimer's disease including focal presentations. Semin Neurol. 39:213–226. 2019. View Article : Google Scholar : PubMed/NCBI

194 

Cummings JL, Tong G and Ballard C: Treatment combinations for Alzheimer's disease: Current and future pharmacotherapy options. J Alzheimers Dis. 67:779–794. 2019. View Article : Google Scholar : PubMed/NCBI

195 

Abbott A: Is 'friendly fire' in the brain provoking Alzheimer's disease? Nature. 556:426–428. 2018. View Article : Google Scholar : PubMed/NCBI

196 

Zhang Y, Dong Z and Song W: NLRP3 inflammasome as a novel therapeutic target for Alzheimer's disease. Signal Transduct Target Ther. 5:372020. View Article : Google Scholar : PubMed/NCBI

197 

Ising C, Venegas C, Zhang S, Scheiblich H, Schmidt SV, Vieira-Saecker A, Schwartz S, Albasset S, McManus RM, Tejera D, et al: NLRP3 inflammasome activation drives tau pathology. Nature. 575:669–673. 2019. View Article : Google Scholar : PubMed/NCBI

198 

Srinivasan S, Kancheva D, De Ren S, Saito T, Jans M, Boone F, Vandendriessche C, Paesmans I, Maurin H, Vandenbroucke RE, et al: Inflammasome signaling is dispensable for ß-amyloid-induced neuropathology in preclinical models of Alzheimer's disease. Front Immunol. 15:13234092024. View Article : Google Scholar

199 

Dobson R and Giovannoni G: Multiple sclerosis-a review. Eur J Neurol. 26:27–40. 2019. View Article : Google Scholar

200 

Inoue M, Williams KL, Gunn MD and Shinohara ML: NLRP3 inflammasome induces chemotactic immune cell migration to the CNS in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA. 109:10480–10485. 2012. View Article : Google Scholar : PubMed/NCBI

201 

Zhao Y, Zhang X, Chen X and Wei Y: Neuronal injuries in cerebral infarction and ischemic stroke: From mechanisms to treatment (Review). Int J Mol Med. 49:152022. View Article : Google Scholar :

202 

Zhao J, Piao X, Wu Y, Liang S, Han F, Liang Q, Shao S and Zhao D: Cepharanthine attenuates cerebral ischemia/reperfusion injury by reducing NLRP3 inflammasome-induced inflammation and oxidative stress via inhibiting 12/15-LOX signaling. Biomed Pharmacother. 127:1101512020. View Article : Google Scholar : PubMed/NCBI

203 

Wang H, Zhong D, Chen H, Jin J, Liu Q and Li G: NLRP3 inflammasome activates interleukin-23/interleukin-17 axis during ischaemia-reperfusion injury in cerebral ischaemia in mice. Life Sci. 227:101–113. 2019. View Article : Google Scholar : PubMed/NCBI

204 

Silveira LS, Antunes Bde M, Minari AL, Dos Santos RV, Neto JC and Lira FS: Macrophage polarization: Implications on metabolic diseases and the role of exercise. Crit Rev Eukaryot Gene Expr. 26:115–132. 2016. View Article : Google Scholar : PubMed/NCBI

205 

Luo L, Liu M, Fan Y, Zhang J, Liu L, Li Y, Zhang Q, Xie H, Jiang C, Wu J, et al: Intermittent theta-burst stimulation improves motor function by inhibiting neuronal pyroptosis and regulating microglial polarization via TLR4/NFκB/NLRP3 signaling pathway in cerebral ischemic mice. J Neuroinflammation. 19:1412022. View Article : Google Scholar

206 

Ye X, Shen T, Hu J, Zhang L, Zhang Y, Bao L, Cui C, Jin G, Zan K, Zhang Z, et al: Purinergic 2X7 receptor/NLRP3 pathway triggers neuronal apoptosis after ischemic stroke in the mouse. Exp Neurol. 292:46–55. 2017. View Article : Google Scholar : PubMed/NCBI

207 

Seok JK, Kang HC, Cho YY, Lee HS and Lee JY: Therapeutic regulation of the NLRP3 inflammasome in chronic inflammatory diseases. Arch Pharm Res. 44:16–35. 2021. View Article : Google Scholar : PubMed/NCBI

208 

Liu W, Guo W, Wu J, Luo Q, Tao F, Gu Y, Shen Y, Li J, Tan R, Xu Q and Sun Y: A novel benzo(d)imidazole derivate prevents the development of dextran sulfate sodium-induced murine experimental colitis via inhibition of NLRP3 inflammasome. Biochem Pharmacol. 85:1504–1512. 2013. View Article : Google Scholar : PubMed/NCBI

209 

Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, D'Agostino D, Planavsky N, Lupfer C, Kanneganti TD, et al: The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 21:263–269. 2015. View Article : Google Scholar : PubMed/NCBI

210 

Yan CY, Ouyang SH, Wang X, Wu YP, Sun WY, Duan WJ, Liang L, Luo X, Kurihara H, Li YF and He RR: Celastrol ameliorates propionibacterium acnes/LPS-induced liver damage and MSU-induced gouty arthritis via inhibiting K63 deubiquitination of NLRP3. Phytomedicine. 80:1533982021. View Article : Google Scholar

211 

Li M, Liu H, Shao H, Zhang P, Gao M, Huang L, Shang P, Zhang Q, Wang W and Feng F: Glyburide attenuates B(a)p and LPS-induced inflammation-related lung tumorigenesis in mice. Environ Toxicol. 36:1713–1722. 2021. View Article : Google Scholar : PubMed/NCBI

212 

Yang G, Lee HE, Moon SJ, Ko KM, Koh JH, Seok JK, Min JK, Heo TH, Kang HC, Cho YY, et al: Direct binding to NLRP3 pyrin domain as a novel strategy to prevent NLRP3-driven inflammation and gouty arthritis. Arthritis Rheumatol. 72:1192–1202. 2020. View Article : Google Scholar : PubMed/NCBI

213 

Jiang H, He H, Chen Y, Huang W, Cheng J, Ye J, Wang A, Tao J, Wang C, Liu Q, et al: Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders. J Exp Med. 214:3219–3238. 2017. View Article : Google Scholar : PubMed/NCBI

214 

He Y, Varadarajan S, Muñoz-Planillo R, Burberry A, Nakamura Y and Núñez G: 3,4-methylenedioxy-β-nitrostyrene inhibits NLRP3 inflammasome activation by blocking assembly of the inflammasome. J Biol Chem. 289:1142–1150. 2014. View Article : Google Scholar

215 

Juliana C, Fernandes-Alnemri T, Wu J, Datta P, Solorzano L, Yu JW, Meng R, Quong AA, Latz E, Scott CP and Alnemri ES: Anti-inflammatory compounds parthenolide and Bay 11-7082 are direct inhibitors of the inflammasome. J Biol Chem. 285:9792–9802. 2010. View Article : Google Scholar : PubMed/NCBI

216 

Kerr ID, Lee JH, Farady CJ, Marion R, Rickert M, Sajid M, Pandey KC, Caffrey CR, Legac J, Hansell E, et al: Vinyl sulfones as antiparasitic agents and a structural basis for drug design. J Biol Chem. 284:25697–25703. 2009. View Article : Google Scholar : PubMed/NCBI

217 

Lee HE, Yang G, Kim ND, Jeong S, Jung Y, Choi JY, Park HH and Lee JY: Targeting ASC in NLRP3 inflammasome by caffeic acid phenethyl ester: A novel strategy to treat acute gout. Sci Rep. 6:386222016. View Article : Google Scholar : PubMed/NCBI

218 

Linton SD: Caspase inhibitors: a pharmaceutical industry perspective. Curr Top Med Chem. 5:1697–1717. 2005. View Article : Google Scholar : PubMed/NCBI

219 

Dinarello CA, Simon A and van der Meer JW: Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov. 11:633–652. 2012. View Article : Google Scholar : PubMed/NCBI

220 

Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, et al: Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 377:1119–1131. 2017. View Article : Google Scholar : PubMed/NCBI

221 

Neudecker V, Haneklaus M, Jensen O, Khailova L, Masterson JC, Tye H, Tye H, Biette K, Jedlicka P, Brodsky KS, et al: Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome. J Exp Med. 214:1737–1752. 2017. View Article : Google Scholar : PubMed/NCBI

222 

Feng Z, Qi S, Zhang Y, Qi Z, Yan L, Zhou J, He F, Li Q, Yang Y, Chen Q, et al: Ly6G+ neutrophil-derived miR-223 inhibits the NLRP3 inflammasome in mitochondrial DAMP-induced acute lung injury. Cell Death Dis. 8:e31702017. View Article : Google Scholar : PubMed/NCBI

223 

Li X, Zhang Y, Zhang H, Liu X, Gong T, Li M, Sun L, Ji G, Shi Y, Han Z, et al: miRNA-223 promotes gastric cancer invasion and metastasis by targeting tumor suppressor EPB41L3. Mol Cancer Res. 9:824–833. 2011. View Article : Google Scholar : PubMed/NCBI

224 

Bandyopadhyay S, Lane T, Venugopal R, Parthasarathy PT, Cho Y, Galam L, Lockey R and Kolliputi N: MicroRNA-133a-1 regulates inflammasome activation through uncoupling protein-2. Biochem Biophys Res Commun. 439:407–412. 2013. View Article : Google Scholar : PubMed/NCBI

225 

Li S, Liang X, Ma L, Shen L, Li T, Zheng L, Sun A, Shang W, Chen C, Zhao W and Jia J: MiR-22 sustains NLRP3 expression and attenuates H. pylori-induced gastric carcinogenesis. Oncogene. 37:884–896. 2018. View Article : Google Scholar

226 

Li D, Yang H, Ma J, Luo S, Chen S and Gu Q: MicroRNA-30e regulates neuroinflammation in MPTP model of Parkinson's disease by targeting Nlrp3. Hum Cell. 31:106–115. 2018. View Article : Google Scholar

227 

Zhou Y, Lu M, Du RH, Qiao C, Jiang CY, Zhang KZ, Ding JH and Hu G: MicroRNA-7 targets Nod-like receptor protein 3 inflammasome to modulate neuroinflammation in the pathogenesis of Parkinson's disease. Mol Neurodegener. 11:282016. View Article : Google Scholar : PubMed/NCBI

228 

Boxberger N, Hecker M and Zettl UK: Dysregulation of inflammasome priming and activation by MicroRNAs in human immune-mediated diseases. J Immunol. 202:2177–2187. 2019. View Article : Google Scholar : PubMed/NCBI

229 

Tezcan G, Martynova EV, Gilazieva ZE, McIntyre A, Rizvanov AA and Khaiboullina SF: MicroRNA post-transcriptional regulation of the NLRP3 inflammasome in immunopathologies. Front Pharmacol. 10:4512019. View Article : Google Scholar : PubMed/NCBI

230 

Zhou T, Xiang DK, Li SN, Yang LH, Gao LF and Feng C: MicroRNA-495 ameliorates cardiac microvascular endothelial cell injury and inflammatory reaction by suppressing the NLRP3 inflammasome signaling pathway. Cell Physiol Biochem. 49:798–815. 2018. View Article : Google Scholar : PubMed/NCBI

231 

Cyranoski D: CRISPR gene-editing tested in a person for the first time. Nature. 539:4792016. View Article : Google Scholar : PubMed/NCBI

232 

Ran FA, Cong L, Yan WX, Scott DA, Gootenberg JS, Kriz AJ, Zetsche B, Shalem O, Wu X, Makarova KS, et al: In vivo genome editing using Staphylococcus aureus Cas9. Nature. 520:186–191. 2015. View Article : Google Scholar : PubMed/NCBI

233 

Bengtsson NE, Hall JK, Odom GL, Phelps MP, Andrus CR, Hawkins RD, Hauschka SD, Chamberlain JR and Chamberlain JS: Muscle-specific CRISPR/Cas9 dystrophin gene editing ameliorates pathophysiology in a mouse model for Duchenne muscular dystrophy. Nat Commun. 8:144542017. View Article : Google Scholar : PubMed/NCBI

234 

Xu C, Lu Z, Luo Y, Liu Y, Cao Z, Shen S, Li H, Liu J, Chen K, Chen Z, et al: Targeting of NLRP3 inflammasome with gene editing for the amelioration of inflammatory diseases. Nat Commun. 9:40922018. View Article : Google Scholar : PubMed/NCBI

235 

Wang YC, Liu QX, Zheng Q, Liu T, Xu XE, Liu XH, Gao W, Bai XJ and Li ZF: Dihydromyricetin alleviates sepsis-induced acute lung injury through inhibiting NLRP3 inflammasome-dependent pyroptosis in mice model. Inflammation. 42:1301–1310. 2019. View Article : Google Scholar : PubMed/NCBI

236 

Tang F, Fan K, Wang K and Bian C: Amygdalin attenuates acute liver injury induced by D-galactosamine and lipopolysaccharide by regulating the NLRP3, NF-κB and Nrf2/NQO1 signalling pathways. Biomed Pharmacother. 111:527–536. 2019. View Article : Google Scholar : PubMed/NCBI

237 

Zhao Q, Bi Y, Guo J, Liu YX, Zhong J, Pan LR, Tan Y and Yu XJ: Pristimerin protects against inflammation and metabolic disorder in mice through inhibition of NLRP3 inflammasome activation. Acta Pharmacol Sin. 42:975–986. 2021. View Article : Google Scholar :

238 

Shi J, Xia Y, Wang H, Yi Z, Zhang R and Zhang X: Piperlongumine Is an NLRP3 Inhibitor With Anti-inflammatory Activity. Front Pharmacol. 12:8183262021. View Article : Google Scholar

239 

Zhao J, Liu H, Hong Z, Luo W, Mu W, Hou X, Xu G, Fang Z, Ren L, Liu T, et al: Tanshinone I specifically suppresses NLRP3 inflammasome activation by disrupting the association of NLRP3 and ASC. Mol Med. 29:842023. View Article : Google Scholar : PubMed/NCBI

240 

Liao T, Ding L, Wu P, Zhang L, Li X, Xu B, Zhang H, Ma Z, Xiao Y and Wang P: Chrysin attenuates the NLRP3 inflammasome cascade to reduce synovitis and pain in KOA rats. Drug Des Devel Ther. 14:3015–3027. 2020. View Article : Google Scholar : PubMed/NCBI

241 

Liu B and Yu J: Anti-NLRP3 inflammasome natural compounds: An update. Biomedicines. 9:1362021. View Article : Google Scholar : PubMed/NCBI

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March-2025
Volume 55 Issue 3

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Spandidos Publications style
Wang H, Ma L, Su W, Liu Y, Xie N and Liu J: NLRP3 inflammasome in health and disease (Review). Int J Mol Med 55: 48, 2025.
APA
Wang, H., Ma, L., Su, W., Liu, Y., Xie, N., & Liu, J. (2025). NLRP3 inflammasome in health and disease (Review). International Journal of Molecular Medicine, 55, 48. https://doi.org/10.3892/ijmm.2025.5489
MLA
Wang, H., Ma, L., Su, W., Liu, Y., Xie, N., Liu, J."NLRP3 inflammasome in health and disease (Review)". International Journal of Molecular Medicine 55.3 (2025): 48.
Chicago
Wang, H., Ma, L., Su, W., Liu, Y., Xie, N., Liu, J."NLRP3 inflammasome in health and disease (Review)". International Journal of Molecular Medicine 55, no. 3 (2025): 48. https://doi.org/10.3892/ijmm.2025.5489