Cytokines are soluble proteins or glycoproteins with low molecular weight, typically ranging from 6 to 70 kDa, that facilitate intercellular signal transmission and serve crucial roles in regulating physiological processes such as immune responses, cell proliferation, differentiation, metabolism, apoptosis and tissue repair (8). These molecules are secreted by immune cells, including macrophages, lymphocytes and mast cells, as well as by non-immune cells such as endothelial cells, fibroblasts, astrocytes, microglia and other stromal cells (8).

The cytokine family is diverse and can be categorized based on structural characteristics and functional roles. Structurally, cytokines are classified into families, including TNF, IL, IFN, colony-stimulating factor (CSF), TGF, chemokines and GF (9). Furthermore, cytokines are categorized into pro- and anti-inflammatory factors based on their primary biological effects. This classification is not definitive as certain cytokines, including TGF-β1, IL-6 and IL-10, may display both pro- and anti-inflammatory characteristics depending on the specific microenvironment (9).

Pro-inflammatory cytokines, including members of the IL-1 family, TNF-α, IL-6, IL-8, IL-12, IL-17, IL-18, IFN-γ and resistin, are pivotal in initiating inflammatory responses. However, the persistent presence or upregulation of these cytokines can result in chronic inflammation, which is associated with aging and various age-related diseases, such as cardiovascular disease, diabetes and Alzheimer's disease (AD). Conversely, anti-inflammatory cytokines, such as IL-4, IL-10, TGF-β, IL-13 and IL-1 receptor antagonist (IL-1RA), typically decline during the aging process, promoting the development of chronic low-grade inflammation and accelerating the aging process (10).

Beyond the classical pro- and anti-inflammatory dichotomy, other families of cytokines and signaling molecules play key roles in intercellular communication and tissue homeostasis. GF, such as nerve GF (NGF), vascular endothelial GF (VEGF), insulin-like GF 1 (IGF-1), neuregulin (NRG), and fibroblast GF, are typically not categorized as either anti-inflammatory or pro-inflammatory (11). As the aging process advances, the levels of GF generally diminish, leading to a marked decrease in the capacity for tissue repair and regeneration. Furthermore, chemokines and CSFs do not directly amplify or inhibit the inflammatory response but primarily modulate immune cell functions (12).

Based on their function, chemokines are classified into inflammatory and homeostatic categories. Inflammatory chemokines enhance the inflammatory response by recruiting immune cells to sites of inflammation and include molecules such as monocyte chemoattractant protein-1 (MCP-1), fractalkine and macrophage inflammatory protein-1 (13). homeostatic chemokines serve a key role in regulating the migration of immune cells, attenuating immune responses, maintaining immune homeostasis and facilitating tissue repair. Key chemokines in this category include CXCL12, CCL18 and CXCL13 (14).

During the aging process, there is a marked elevation in the levels of pro-inflammatory factors, including IL-6, TNF-α, and IL-1β. These factors contribute to the maintenance of chronic low-grade inflammation by facilitating the activation of immune cells and perpetuating the cytokine cascade (15). For example, IL-6 overexpression in collagen-induced arthritis mice and immunoglobulin heavy chain enhancer (Eµ)-IL-6 transgenic mice promotes inflammation via nuclear factor IL-6-driven transcription (16). Moreover, elevated serum IL-6 in humans is associated with cardiovascular disease and type 2 diabetes (17). TNF-α, primarily acting via NF-κB, contributes to aging-associated pathologies such as muscle atrophy and neurodegeneration. This is supported by studies in LPS-stimulated primary murine macrophages and C57BL/6 mice, where TNF/TNF receptor 1 (TNFR1) ablation alleviates lethality caused by NF-κB pathway deficiency (18,19). Inflammatory chemokines are also upregulated with age, promoting monocyte, macrophage and T cell recruitment to inflamed sites (20). Their continuous elevation sustains chronic inflammation and worsens age-associated diseases (13).

Under physiological conditions, anti-inflammatory factors are crucial for maintaining immune system balance and homeostasis by mitigating excessive immune responses. During aging, the expression of key anti-inflammatory cytokines such as IL-10 and IL-1RA is typically diminished (21). This compromises the immune system capacity to resolve inflammation. Specifically, lower serum IL-10 levels, as observed in a cross-sectional study of 193 adults aged >60 years, impair the suppression of excessive immune responses and are associated with features of metabolic syndrome (22). Similarly, decreased IL-1RA expression leads to heightened activity of the pro-inflammatory cytokines IL-1α and IL-1β (23,24). By contrast, TGF-β undergoes a functional shift rather than a quantitative decline. Although TGF-β serves crucial roles in tissue repair and immune regulation, its signaling becomes dysregulated with age (25). This results in overactivation of the TGF-β pathway, which is associated with pro-fibrotic responses and contributes to tissue senescence and pathological fibrosis, thereby exacerbating chronic inflammation (26).

Throughout the aging process, GF levels typically decrease, which directly impacts tissue repair, cellular regeneration and immune system functionality (27). To clarify their distinct roles in the aging-associated decline, major GFs can be categorized into two functional groups based on their primary physiological actions: Neurotrophic and angiogenic factors, which support neuronal survival and vascular health, and metabolic and repair-associated factors, which regulate tissue maintenance and regeneration.

As individuals age, the concentration of NGF diminishes (28). A deficiency in NGF during aging, as modeled in AD11 anti-NGF transgenic mice, contributes to neurodegeneration resembling AD (29). Similarly, the levels of VEGF typically decrease with age, which is associated with vascular aging and inadequate tissue oxygenation (30). This can lead to compromised vascular endothelial cell function, thereby impairing tissue repair and regeneration (30). Thus, the decrease in VEGF levels is a notable contributor to age-related declines in vascular function and associated disease, such as cardiovascular disorders (31).

As aging progresses, levels of IGF-1 diminish (32), which can directly impair tissue repair and regeneration, adversely affecting immune function and disease resistance, thereby elevating the risk of infection and illnesses in the elderly population (33). NRG facilitates neuronal survival, migration and synaptic function through interaction with erythroblastic oncogene B (ErbB) receptors (34). With advancing age, NRG expression typically decreases, particularly in ND, and a deficiency in NRG levels markedly impairs neural repair (35). Furthermore, the decrease in NRG levels not only impacts the development of the nervous system but may also exacerbate the progression of ND, thereby accelerating the deterioration of neural function. However, in certain pathological contexts such as AD, regional upregulation of the NRG receptor Erb-B2 receptor tyrosine kinase 4 (ErbB4) has been reported, suggesting a complex, disease stage-dependent regulation (36).

The concentration of M-CSF exhibits a positive association with age (37). M-CSF is key in the development and functionality of macrophages, promoting the survival, proliferation and differentiation of mononuclear phagocytes (38). As individuals age, elevated M-CSF levels may enhance macrophage activity, intensifying inflammatory responses (39). Given the critical role of macrophages in pathogen elimination, clearance of damaged cells and facilitation of tissue repair, increased M-CSF levels may contribute to a heightened incidence of inflammatory diseases, thereby worsening age-associated health issues (37).

In chronic low-grade inflammation, as a compensatory mechanism for the declining immune system, levels of G-CSF and GM-CSF rise. This elevation leads to increased production of immune cells, such as neutrophils and macrophages, thereby enhancing immune efficacy. These changes increase the susceptibility of elderly individuals to inflammatory phenomena (40).

Inflammatory senescence is a hallmark of aging, characterized by prolonged immune system activation and a persistent increase in pro-inflammatory factors (41). One of the key mechanisms underlying inflammatory aging is the activation of inflammasomes, which initiate a sustained immune response by promoting the release of pro-inflammatory cytokines such as IL-1β and IL-18 (42). This persistent pro-inflammatory response not only exacerbates tissue damage but also contributes to a decline in immune function (41). Chronic activation of inflammasomes accelerates the aging process and is closely associated with the onset of age-related diseases such as AD, atherosclerosis, and type 2 diabetes (43). Therefore, the continuous activation of inflammasomes is a key driver of age-related immune decline and disease progression.

As aging advances, the intracellular levels of reactive oxygen species (ROS) increase. ROS not only directly damage cell components but also function as signaling molecules to activate the NOD-like receptor protein 3 (NLRP3) inflammasome. In murine bone marrow-derived macrophages, ATP-induced oxidative stress upregulates NLRP3 expression and promotes its cytoplasmic aggregation, thereby activating Caspase-1 and driving IL-1β/IL-18 secretion (44). During aging, mitochondrial function declines, and the damage signals released by mitochondria, such as cytochrome C, activate the NLRP3 inflammasome (45). Concurrently, the increase in mitochondrial peroxides augments ROS production, thereby promoting inflammasome activation (46). Senescent cells typically exhibit damage or leakage of the cell membrane, resulting in the release of intracellular endogenous harmful molecules, such as ATP and uric acid crystals, into the extracellular environment. These molecules serve as danger signals, activating the NLRP3 inflammasome in immune cells and triggering an immune response (47).

During the aging process, the activation of inflammasomes not only influences the immune response through intrinsic mechanisms but also intensifies the inflammatory response by engaging cellular signaling pathways, such as the NF-κB, MAPK, JAK/STAT, phosphoinositide 3-kinase (PI3K)/Akt and Nrf2) signaling pathways.

NF-κB serves as a key transcription factor that governs physiological processes such as immune response, cell proliferation, survival and aging (48). Inflammasomes initiate a cascade of reactions via the activation of NLRP3, thereby facilitating the upregulation of pro-inflammatory cytokines, including IL-1β, IL-6 and TNF-α. This process is predominantly mediated by the regulatory function of the NF-κB signaling pathway (49,50). The activation of NLRP3 results in degradation of IκB, an inhibitor of NF-κB, thereby alleviating the suppression of NF-κB. This facilitates translocation of NF-κB into the nucleus, where it initiates the transcription of genes associated with inflammation (51). Prolonged activation of NF-κB sustains the pro-inflammatory response in immune cells and may contribute to the progression of aging-associated diseases. Consistent with this, NF-κB activation has been identified as a key mediator of synaptic repair in early-stage AD mouse models (52,53).

MAPK signaling pathway is a key pathway in cell response to external stimuli, involving cell proliferation, differentiation, survival and death (54). NLRP3 inflammasome activates JNK and p38 MAPK through stress signals such as ROS, enhances the secretion of IL-6, TNF-α and other pro-inflammatory factors and maintains and aggravates chronic low-grade inflammation (55). This ROS-MAPK-NLRP3 axis has been validated in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) mouse model, where its inhibition alleviates neuroinflammation and motor deficit (56). Overactivation of MAPK signaling increases cellular oxidative stress, promotes the aging process and serves a key role in aging-associated diseases, such as PD (57).

The JAK/STAT signaling pathway serves a key role in cytokine signal transduction, primarily regulating cell proliferation, differentiation, immune responses and senescence (58). In aging, the JAK/STAT pathway is activated by pro-inflammatory cytokines, such as IL-6 and TNF-α, thereby amplifying the immune cell response to inflammation, perpetuating chronic inflammation and accelerating the aging process (59). Dysregulation of this pathway is associated with immune system disorders, particularly in aging-associated diseases such as NDs, cardiovascular disease and diabetes. Metabolic stressors can exacerbate inflammation by augmenting JAK/STAT signaling, directly linking this pathway to the pathophysiology of multiple age-related conditions, such as rheumatoid arthritis, atherosclerosis, and PD (60,61).

The PI3K/Akt signaling pathway is key to the regulation of cell survival, proliferation and metabolism and it plays a crucial role in cellular adaptation to stress. While the PI3K/Akt pathway typically exerts an anti-inflammatory effect by inhibiting pro-inflammatory pathways, its prolonged activation may contribute to chronic low-grade inflammation during aging (62). Concurrently, the NLRP3 inflammasome can activate the PI3K/Akt pathway via pro-inflammatory factors, such as IL-6, which are upregulated by the NF-κB signaling pathway, thereby enhancing cytokine secretion and perpetuating chronic low-grade inflammation (63). Excessive activation of the PI3K/Akt pathway may result in the persistence of inflammatory responses, contributing to age-associated metabolic disorders and diminished immune function. In BV-2 murine microglial cells and a transient middle cerebral artery occlusion/reperfusion (tMCAO/R) mouse model of cerebral ischemia-reperfusion, modulation of this pathway directly regulates microglial phenotype and autophagic activity (64).

Nrf2 serves as a key transcription factor in cell antioxidant defense mechanisms, primarily sustaining redox homeostasis via the regulation of antioxidant enzyme expression, including heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (65). Throughout aging, oxidative stress accumulation stimulates Nrf2 activation, thereby augmenting the cell antioxidant capacity (66). In the context of chronic low-grade inflammation, Nrf2 mitigates the accumulation of ROS and lipid peroxidation by modulating the expression of antioxidant genes, which in turn attenuates the activation of NLRP3 inflammasomes (67). Concurrently, Nrf2 suppresses excessive immune responses by upregulating anti-inflammatory factors, such as IL-10 (68). Conversely, during aging, the regulation of Nrf2 becomes impaired. This impairment is driven by upstream factors such as the upregulation of glycogen synthase kinase-3β and leads to a functional decline compromising the cellular responsiveness to oxidative stress, as demonstrated in aged C57BL/6 mouse models of hepatic ischemia-reperfusion injury and senescent L02 hepatocytes (69,70) (Fig. 2).

TGF-β is a pleiotropic cytokine involved in immune regulation, cell proliferation and aging (71). During aging, TGF-β signaling becomes dysregulated, contributing to chronic low-grade inflammation and fibrosis (72). Within the inflammatory network, TGF-β positively modulatse immune responses via Smad-dependent pathways (73). Moreover, it acts with NF-κB and MAPK signaling to promote tissue remodeling. Activation of the NLRP3 inflammasome may exacerbate fibrosis by upregulating TGF-β expression (74).

Neuroinflammation has been reported to result in the activation of inflammatory cells within the brain, primarily microglia and astrocytes (75). Concurrently, factors such as immune senescence, mitochondrial dysfunction, autophagy and dysfunction of the ubiquitin-proteasome system contribute to a sustained state of chronic inflammation (76). In this activated state, inflammatory cells release cytokines, which are implicated in the pathogenesis of various types of ND (77), including AD and PD, by inducing neuronal synaptic dysfunction and excitotoxicity.

Under physiological conditions, microglia exhibit phagocytic activity, facilitating the removal of damaged neurons and promoting tissue repair. Concurrently, astrocytes contribute to neuroprotection by clearing debris from the cerebrospinal fluid. During neuroinflammation, IL-1 secreted by activated microglia and astrocytes engages MAPK signaling, leading to upregulation of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and enhanced Aβ formation (78). IL-1 also promotes τ hyperphosphorylation, contributing to neurofibrillary tangle (NFT) pathology, as evidenced by elevated p38 MAPK expression in IL-1β-infused rat brain (79). τ protein is key for the growth and development of neuronal axons, serving as an essential molecule for the assembly and stabilization of the microtubule cytoskeleton (80). In AD, hyperphosphorylated τ proteins are major components of paired helical filaments, establishing a connection to NFTs (81). Furthermore, IL-4 has been shown to impede Aβ clearance, resulting in increased Aβ deposition and amyloid plaque formation (82-84). This is evidenced by experiments in 4-month-old amyloid precursor protein (APP) transgenic TgCRND8 mice with pre-existing plaques (82). Overexpression of murine IL-4 in the hippocampus via adeno-associated virus 2/1 chimeric vector (AAV2/1) notably aggravates cerebral Aβ deposition and plaque burden (82,85).

In addition to their pro-inflammatory role, microglia and astrocytes produce immunosuppressive factors to limit inflammation (86). For example, IL-10 is upregulated in the rat cerebral cortex following LPS injection, with increased mRNA at 8 and protein expression at 24 h post-injection (87). IL-10 has been demonstrated to induce the expression of anti-inflammatory microRNAs, which negatively regulate toll-like receptor (TLR) signaling pathways and modify the stability of inflammatory cytokine mRNA (88).

There are two primary categories of cell death: Accidental cell death (ACD) and programmed cell death (PCD). ACD occurs as a reaction to unforeseen injurious stimuli, such as necrosis (89). By contrast, PCD is an orderly process of self-extinction initiated by gene regulation. PCD occurs in a spatially and temporally constrained manner during normal neuronal development, facilitating the establishment of neural structures and shaping the central nervous system (CNS) (90,91). In the pathogenesis of nervous system disease, anomalies in the signaling cascades of PCD, including apoptosis, ferroptosis, autophagy, pyroptosis and necroptosis, are evident (92,93).

Pyroptosis is characterized by cell rupture and the release of cell contents, which leads to abnormal microglial activation, intense inflammation and the promotion of ND (94). Pyroptosis is primarily induced by inflammasome activation (NLRP3) triggered by pathological factors such as mitochondrial dysfunction, ROS accumulation or Aβ during aging. Upon activation, Caspase-1 cleaves gasdermin D, whose N-terminal fragment forms membrane pores, leading to cell swelling, rupture and release of pro-inflammatory cytokines (95,96). Caspase-1 cleaves pro-IL-1β and pro-IL-18 into their mature forms, amplifying inflammation (96). Damage-associated molecular patterns (DAMPs) released by pyrocytes initiate inflammatory responses in adjacent glial cells via interaction with TLR4 or purinergic ligand-gated ion channel 7 receptors, potentially leading to further neuronal damage (97).

Iron-dependent cell death, also known as ferroptosis, represents a distinct form of PCD characterized by iron accumulation in cells (98). This process leads to neuronal damage and cell death through iron-mediated lipid peroxidation. Aging is associated with disruptions in cell iron homeostasis, resulting in iron overload and the generation of excessive ROS via the Fenton reaction (98,99). These ROS oxidize lipids, compromising the integrity of the cell membrane (100). Excessive ROS activate NF-κB, leading to the formation of inflammasomes and the release of pro-inflammatory cytokines such as IL-6, TNF-α and IL-1β, which contribute to neuroinflammation (101). Hepcidin, a peptide hormone involved in iron homeostasis, inhibits cell iron efflux by interacting with ferroportin 1 (102). Hepcidin levels are associated with IL-6, which promotes hepcidin expression, thereby increasing intracellular iron levels. Ferritin, an iron storage protein, is upregulated during inflammation via the IL-6/STAT3 pathway (103). Additionally, IL-1β, IL-6 and TNF-α can indirectly induce ferritin synthesis by enhancing hepcidin transcription.

Necrosis was initially identified as an alternative pathway to the death receptor pathway (104). In cell death due to ischemia, physical injury, oxidative stress or pathogen infection, the integrity of the cell membrane is compromised, leading to the release of DAMPs and the activation of immune cells, such as microglia and astrocytes, via pattern recognition receptors. This triggers downstream inflammatory signaling pathways (105). DAMPs trigger the formation of the NLRP3 inflammasome complex through ROS-dependent pathways and promote the maturation and secretion of pro-inflammatory cytokines such as IL-1β and IL-18 via caspase-1-dependent mechanisms (106). High mobility group box 1 (HMGB1), a nuclear protein, is released into the extracellular environment during ACD (107). While HMGB1 has limited direct pro-inflammatory effects, it indirectly enhances the release of pro-inflammatory cytokines by recruiting inflammatory cells such as microglia (108). Under the influence of microglia-derived IL-1α, TNF-α and complement component 1, q subcomponent, astrocytes transform into A1-reactive astrocytes (109). These A1-reactive astrocytes produce CXCL10, which facilitates immune cell infiltration and enables immune cells to cross the blood-brain barrier (BBB) into the CNS, exacerbating neuroinflammation (110).

The BBB serves as a key protective mechanism within the CNS, comprising endothelial cells, pericytes, astrocytic end-feet and a basement membrane. Under physiological conditions, the BBB is notably impermeable; however, in pathological states, the release of vasoactive substances, cytokines and chemical mediators enhances its permeability, thereby compromising its barrier function (111). Damage to the BBB may be associated with the onset of age-associated ND and the deterioration of cognitive function (111-113).

The activation, migration and cytokine release by some immune cells can compromise the integrity of the BBB. Compromised BBB permits the entry of peripheral fibrinogen into the brain, which activates microglia and promotes neuroinflammation (114). During aging, the activation of microglia and astrocytes upregulates MMP activity, resulting in the degradation of tight junction proteins and increased BBB permeability (115). Furthermore, BBB damage facilitates the entry of neurotoxic substances, including plasma protein, inflammatory cells and toxins, into the brain parenchyma, thereby inducing neuroinflammation and neuronal damage (116). In conclusion, aging compromises the integrity of the BBB via endothelial damage and neuroinflammation. This leads to BBB leakage, which exacerbates inflammation and neurodegeneration in the brain, thereby establishing a deleterious feedback loop.

AD is a prevalent neurodegenerative disorder among the elderly, current estimates suggest that 44 million people live with dementia worldwide at present (117). This is predicted to more than triple by 2050 as the population ages. Primarily characterized by cognitive decline, memory impairment, language disturbance and behavioral alteration. The hallmark pathological features of AD include the deposition of Aβ, primarily in the cerebral cortex and hippocampal regions, leading to the formation of amyloid plaques, abnormal phosphorylation of τ protein, resulting in NFTs that compromise neuronal structure and function (118), and neuroinflammation, with extensive research indicating that the inflammatory response is a predominant mechanism in the pathogenesis of AD (119,120).

Microglia and astrocytes are capable of initiating an inflammatory response following an injury to the CNS. Aβ rapidly activates microglia, resulting in alteration to their morphological and phenotypical characteristics, which promote phagocytosis and induce localized immune cells (121). However, sustained microglial activation and unresolved inflammation within the brain are detrimental to neurons and synapses, promoting chronic dysregulation of glial cells and contributing to the deterioration of brain structure and function (122). Aβ42 has been shown to induce microglial phagocytosis of viable neurons, resulting in early synaptic loss in AD (123). Following exposure to Aβ, microglia secrete a range of pro-inflammatory cytokines and chemokines, including IL-6, IL-1β, TNF-α, macrophage inflammatory protein-1α and MCP-1 (124). This secretion leads to the recruitment and activation of astrocytes and peripheral immune cells.

Pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α play a predominant role in exacerbating AD pathology. They not only maintain the inflammatory environment but also directly interact with and aggravate Aβ plaques and NFTs (84). IL-1β is elevated in the brain of patients with AD, particularly in association with diffuse plaques, and is predominantly produced by activated microglia during early disease stages (125). In vitro, IL-1β treatment of human neuroblastoma SH-SY5Y cells enhances APP transcription via NF-κB activation, leading to increased APP synthesis (125). These findings are supported by APP/presenilin 1 (PS1) transgenic mouse models, where IL-1β overexpression is associated with elevated cortical APP levels and accelerated amyloid deposition (125,126). IL-1β also enhances BACE1 and γ-secretase activity via MAPK and JAK/STAT signaling, contributing to Aβ overproduction (127).

Neuroinflammation upregulates BACE1 activity while downregulating the expression of Aβ-degrading enzymes. Inflammatory processes lead to the downregulation of Aβ-degrading enzymes, including insulin-degrading enzyme and neutral endopeptidase, contributing to the accumulation of Aβ in the brain. These effects create a self-reinforcing cycle that accelerates plaque formation (128,129). Moreover, the intermediate form of APP activates microglia, resulting in the excessive secretion of IL-1β, which stimulates astrocytes and promotes the release of pro-inflammatory substances (130).

Another cytokine key to the pathogenesis of neuroinflammation in AD is IL-6 (131). Elevated in the cerebrospinal fluid of patients with AD, IL-6 upregulates pro-inflammatory cytokine production in primary murine microglia and astrocytes, an effect associated with enhanced Aβ plaque deposition and τ pathology in APP/PS1 mice (132). IL-6 promotes acute-phase protein release and vascular permeability in the CNS, amplifying neuroinflammation (133).

TNF-α binding to TNFR1 recruits TNFR1-associated death domain protein, TNFR-associated factor 2/5, receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and cellular inhibitor of apoptosis protein 1/2 (cIAP1/2) to form complex I, leading to canonical NF-κB activation andinflammation (134). When NF-κB activation is blocked (such as by cIAP1/2 inhibition), Caspase-8 is activated, initiating apoptosis (135). If Caspase-8 is suppressed, RIPK1 deubiquitinates and associates with Fas-associated death domain protein (FADD) and receptor-interacting serine/threonine-protein kinase 3 to form complex II, which phosphorylates mixed lineage kinase domain-like pseudokinase and triggers necroptosis, a pro-inflammatory cell death pathway (136,137).

IL-10 suppresses NLRP3 inflammasome activity via STAT3 signaling, decreasing IL-1β release and promoting microglial M2 polarization (138). However, in AD, IL-10 expression is typically decreased, which diminishes its inhibitory effect on excessive inflammatory responses. The impaired anti-inflammatory response fuels chronic neuroinflammation and pathological progression.

As the intercellular signaling proteins that serve as ligands for receptor tyrosine kinases within the ErbB receptor family, NRGs and their corresponding receptors are key to organ development and maintenance, as well as the pathogenesis of NDs (139). Notably, NRG1 may exert a protective effect by modulating the pathological progression of AD. Compared with age-matched normal controls, the immunoreactivity intensities of ErbB4 and phosphorylated ErbB4 are elevated in the neurons of the CA1-2 transition zone in AD brains (36). Furthermore, ErbB4 expression is increased in the medial neurons of the basolateral amygdala cortex and the superior frontal gyrus neurons of patients with AD (36). In the cerebral cortex and hippocampus of APP/PS1 double transgenic mice, ErbB4 immunoreactivity is significantly higher than that in age-matched wild-type controls (36). In APP/PS1 mice, ErbB4 immunoreactivity is elevated in the cerebral cortex and hippocampus compared with wild-type controls (36). These reports suggest that aberrant alterations in ErbB4 may contribute to the pathological progression of AD, while NRG1 exhibits neuroprotective effects against neurotoxicity induced by the Swedish amyloid precursor (36).

NRG1 mitigates the neurotoxic effects associated with the expression of APP C-terminal fragment in SH-SY5Y human neuroblastoma cells, reducing ROS accumulation and mitochondrial membrane potential loss via ErbB4 signaling (140). Another study examined the downstream signaling pathway of NRG1, highlighting its role in counteracting Aβ42-induced neurotoxicity (141). The findings indicate that inhibiting the activation of the PI3K/Akt pathway negates NRG1 ability to prevent Aβ42-induced lactate dehydrogenase release, increases the number of TUNEL-positive cells and elevates ROS accumulation in primary cortical neurons (142). These findings confirm NRG1/PI3K/Akt signaling as a viable therapeutic target for Aβ-induced neurotoxicity in AD (Fig. 3).

Our previous study demonstrated that recombinant Neuregulin-1β treatment alleviates LPS-induced neuroinflammation by reducing the number of microglial cells and astrocytes as well as the expression of IL-1β (143). Moreover, our group recently reported that targeted activation of ErbB4 using the small-molecule agonist 4-bromo-1-hydroxy-2-naphthoic acid (E4A), an NRG1 mimic, exerts neuroprotective effects in multiple disease-related models (144-146). Specifically, E4A alleviates neuronal damage in D-galactose-induced senescence (144), ameliorates cognitive deficit in APP/PS1 mice via dedicator of cytokinesis 3 (DOCK3) signaling (145) and mitigates neuroinflammation in a polystyrene microplastic exposure model (146). These findings not only corroborate the key role of the NRG1-ErbB4 axis in neuronal protection and the regulation of neuroinflammation but also offer direct experimental evidence in support of the cytokine-centered approach for treating AD and other ND.

PD is a neurodegenerative disorder marked by progressive extrapyramidal dysfunction. The primary pathological characteristics of PD include the degeneration of dopaminergic (DAergic) neurons in the substantia nigra (SN), leading to decreased levels of dopamine and the accumulation of α-syn within the cytoplasm and axons of DAergic neurons, forming Lewy bodies (147). Imamura et al (148) identified the infiltration of activated microglial cells in the SN of brain of patients with PD postmortem. These activated microglial cells secrete pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6, and express class II major histocompatibility complex (MHC) molecules. These activated microglial cells contribute to neuronal damage in patients with PD (148). Furthermore, neuroimaging studies employing radioactive tracers specific to microglial cell activation have revealed the presence of persistent neuroinflammation in PD (149,150).

The aggregation of abnormal and insoluble α-syn is key in the pathogenesis of PD (151). Misfolded α-syn serves as a DAMP to dysregulate TLR2/TLR4-myeloid differentiation primary response protein 88-NF-κB signaling in microglia, inducing TNF-α and IL-1β production. Treatment of BV2 mouse or primary microglia with aggregated α-syn upregulates the production of TNF-α, IL-1β, MCP-1 and IFN-γ (152). Additionally, α-syn binding to TLR2 triggers NLRP3 inflammasome activation, promoting IL-1β maturation and release (153). These IL-1β-driven neuroinflammatory responses contribute to DAergic neuron degeneration in PD. Furthermore, the knockout of TLR2 decreases the uptake of α-syn by mouse microglia (154) (Fig. 4).

TLR4-NF-κB activation promotes α-syn sequestration into autophagosomes (155). Inhibition of TLR4 function in BV2 and TLR4 knockout primary mouse microglial cells impedes the uptake of α-syn and suppresses the production of pro-inflammatory cytokines TNF-α and IL-6 (156). Additionally, α-syn upregulates the expression of IFN-γ in microglia, which induces the expression of MHC-I on neurons, thereby enabling selective targeting by CD8⁺ T cells (157). The α-syn (SNCA) gene encodes α-syn and its overexpression in rat models results in reduced fiber density in DAergic neurons and an increased number of MHC-II⁺ microglial cells (158,159). T cells from mice immunized with nitrated α-syn exacerbate neurodegeneration in response to MPTP exposure (160). Furthermore, both type 1 and 17 helper T cells contribute to the enhancement of MPTP-induced neurodegeneration, whereas regulatory T cells exert a neuroprotective effect (161). These results support the role of T cell subsets activated by the immune response induced by α-syn in the pathogenesis of DAergic neurodegeneration. Collectively, these mechanisms establish a chronic neuroinflammatory environment in the PD brain.

TNF-α is upregulated in the mouse striatum prior to DAergic neuron degeneration, implicating it in early PD pathogenesis. Genetic ablation of TNF receptors or pharmacological inhibition of TNF-α (using thalidomide) attenuates MPTP-induced neuronal loss (162,163). A cohort study demonstrated an association between early anti-TNF therapy and decreased PD incidence (164). α-syn binding to TLR2 activates the NLRP3 inflammasome. In patients with PD, NLRP3 colocalizes with microglia in the SN (165). The NLRP3 inhibitor MCC950 attenuates inflammasome activation and mitigates motor deficit, nigrostriatal degeneration and α-syn aggregation in mouse models (165,166). Nrf2 activation by dimethyl fumarate decreases ROS production in neurons of SNCA (p.A53T) transgenic mice and protects against MPTP- and α-syn-induced DAergic neuron damage (167,168). Peroxisome proliferator-activated receptor (PPAR)-γ agonists, such as pioglitazone and rosiglitazone, alleviate MPTP-induced inflammation and protect nigrostriatal function in mice and monkeys; pioglitazone also decreases glial cell activation and prevents DAergic neuron loss in MPTP-treated mice (162,169). Collectively, these findings support targeting TNF-α, NLRP3, Nrf2 and PPAR-γ as therapeutic strategies to impede PD progression.

ALS is a neurodegenerative disorder marked by the progressive degeneration of motor neurons, leading to symptoms such as muscle weakness, atrophy and impaired motor function (163). The pathology of ALS involves the degeneration of both upper and lower motor neurons within the spinal cord and cerebral cortex, culminating in the inability to control muscle movements (164). The resultant motor neuron death precipitates muscle atrophy and weakness, leading to mortality, often due to respiratory failure caused by paralysis of the respiratory muscles (170). Neuroinflammation is a prevalent pathological feature in ALS, regardless of the presence of genetic mutations, and is characterized by the infiltration of activated microglia and astrocytes. These activated glial cells produce pro-inflammatory cytokines, which are upregulated in postmortem tissue of patients with ALS (171).

Aging cells release pro-inflammatory factors such as IL-6, IL-1β and TNF-α through the SASP, which activate glial cells and initiate chronic CNS inflammation (172). In vivo studies demonstrate that systemic administration of recombinant murine IL-6 in C57BL/6 mice promotes microglial polarization toward the M1 phenotype, characterized by elevated CD16/32 expression, and exacerbates neuroinflammation (173-175). IL-6 is a potential therapeutic target for ALS. In superoxide dismutase 1 (SOD1)^G93A transgenic mice, IL-6 promotes microglial M1 polarization via JAK2/STAT3 signaling, resulting in TNF-α and ROS release that directly damages spinal motor neurons (176,177). IL-6 also downregulates glutamate transporter 1, causing excitotoxicity, and impairs the Nrf2 antioxidant pathway, resulting in mitochondrial ROS accumulation and NLRP3 inflammasome activation (178,179). These IL-6-driven processes collectively establish an oxidative-inflammatory cycle that accelerates motor neuron death.

Paralleling the persistent elevation of inflammatory cytokines, a concurrent failure in cell waste disposal mechanisms contributes to proteotoxicity and disease progression in ALS. With advancing age, autophagic function declines, resulting in the inefficient degradation of aberrant proteins, including transactive response DNA-binding protein 43 (TDP-43) and SOD1 aggregates (180). In the SOD1^G93A transgenic mouse model of ALS, these autophagic deficits contribute to motor neuron degeneration. In individuals with ALS, persistent activation of the mechanistic target of rapamycin pathway inhibits autophagy initiation, while mutations in p62/sequestosome-1 compromise substrate recognition (181,182). Additionally, lysosomal acidification disorder, characterized by increased pH, leads to cathepsin inactivation, thereby exacerbating protein toxicity (183).

The inflammatory state in ALS is strengthened and regulated by persistent changes at the epigenetic level. Age-associated DNA methylation loss and abnormal histone modifications upregulate pro-inflammatory genes, while suppressing neuroprotective genes (184). For example, microRNA-155 enhances microglial JAK/STAT signaling by inhibiting suppressor of cytokine signaling 1, whereas the downregulation of microRNA-146a disrupts NF-κB pathway regulation, creating a positive feedback loop that drives ALS progression (185). Pro-inflammatory factors, including IL-1α, TNF-α and complement component 1, q subcomponent, A chain, are released by microglia activated by neuroinflammation, inducing neurotoxicity via alterations in astrocyte activity (109). TNF-α activates the Caspase-8/FADD signaling pathway via TNFR1, while IL-6 upregulates the pro-apoptotic protein Bax via the JAK/STAT3 pathway, both of which are implicated in the pathogenesis of ALS (186) (Fig. 5).

HD is a deleterious autosomal dominant hereditary neurological disorder, characterized by mood disturbance, weight loss, movement abnormality and dementia (187). The gene responsible for HD was first cloned in 1993, and the highly conserved protein it encodes, whose function remains unclear, is huntingtin (HTT) (187,188). In individuals with HD, the polymorphic trinucleotide repeat sequence CAGn at the 5'end of the gene undergoes expansion beyond the normal repeat threshold, leading to the translation of an extended polyglutamine tract within the protein (187). The proteolytic cleavage of the mutant HTT protein plays a critical role in the pathogenesis of HD (189). Studies utilizing in vivo models, such as R6/2 HD mice, demonstrate that these aberrant HTT fragments initiate a complex cascade of compensatory and deleterious molecular processes, including neuroinflammation (190,191). Such processes result in atrophy, fragility and damage to nerve cells, rendering them susceptible to stressors, such as excitotoxic stress, oxidative damage, pro-apoptotic signals, energy depletion, impaired proteolysis and neurophysiological defects. Collectively, these factors may contribute to neuronal death (189).

Compared with other CNS disorders, the involvement of microglia in HD remains insufficiently investigated (192). Singhrao et al (193) demonstrated microglial impairment in patients with HD (193). The aforementioned study observed an increased number of microglial cells in the caudate nucleus and putamen, associated with elevated expression levels of complement factors. Sapp et al (194) investigated microglial morphological alterations associated with HD and identified structurally activated microglia in the cortex, globus pallidus and neostriatum. Notably, in the cortex and striatum, the aggregation of thymosin β-4-reactive microglia intensifies in parallel with the progression of neuropathological grade (194). Another study reported microglial accumulation in HD tissue and the R6/2 mouse model of the striatum (192).

Accumulated HTT expression induces transcriptional alterations in neuronal cells, and it is possible that microglial transcription is similarly impacted (192). Björkqvist et al (195) suggested that postmortem tissue from patients with HD exhibit distinct inflammatory characteristics. Specifically, inflammatory molecules such as TNF-α and IL-1β are markedly elevated in the striatum, whereas MMP-9, IL-6 and IL-8 show increased expression in the cortex and cerebellar regions (192). This contrasts with the neuroinflammatory profiles observed in other types of ND, such as PD or AD, which typically involve the upregulation of a broader range of inflammatory molecules (196). The presence of inflammatory regulators in the striatum may signify ongoing pathological processes, while the dysregulation of molecules such as MMP-9, IL-6 and IL-8 suggests a more generalized role of mutant HTT protein expression (197). Furthermore, studies have demonstrated that monocytes expressing mutant HTT protein in patients with HD exhibit increased secretion of IL-6 (198-200). By contrast with other neurological disorders, including AD and multiple sclerosis, the involvement of peripheral immune cells, such as neutrophils and lymphocytes, in HD has not been thoroughly explored (201). Furthermore, studies have indicated that significant infiltration of T cells is not observed in postmortem tissue of individuals with HD (202,203). Consequently, neuroinflammation in HD is predominantly sustained by the interactions among neurons, microglia and astrocytes (192) (Fig. 6).