Ferroptosis: A potential therapeutic target in autoimmune disease (Review)
- Authors:
- Published online on: June 15, 2023 https://doi.org/10.3892/etm.2023.12067
- Article Number: 368
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Copyright: © Shen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
1. Introduction
Since being named in 2012 by Dixon et al (1), ferroptosis has been probed in a wide range of pathologies and proposed as a novel therapeutic strategy for numerous diseases, including cancer (2,3), ischemia-reperfusion injury (4,5) and neurodegenerative disorder (6,7). Autoimmune disease, particularly rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), insulin-dependent diabetes mellitus (IDDM) and inflammatory bowel disease (IBD) (8,9), are heterogeneous with regard to prevalence, manifestation and pathogenesis. Accumulating evidence in recent times has shown an association of ferroptosis with the pathogenesis and development of autoimmune diseases (10-12). The present review aimed to summarize the association between ferroptosis and autoimmune disease, focusing on potential mechanisms and therapeutic strategies.
2. Overview of ferroptosis
Ferroptosis was proposed in 2012 as a distinctive type of non-apoptotic cell death (1) characterized by iron overload and lipid peroxidation. This differs from other forms of regulated cell death. The primary feature of ferroptosis is mitochondrial shrinkage, which occurs alongside an increase in mitochondrial membrane density and degeneration of mitochondrial crista but with no changes in morphology of the nucleus (1).
Several pathways, including the metabolism of iron, acid and lipid, have been implicated in ferroptosis (13). Excessive cytosolic Fe2+ catalyzes the Fenton reaction and activates iron-dependent metabolic enzymes, leading to production of highly reactive hydroxyl radicals and oxidized polyunsaturated fatty acids (PUFAs), which results in the promotion of the accumulation of lipid reactive oxygen species (ROS) and ferroptosis. The metabolism of amino acids, especially the system Xc/glutathione (GSH)/GSH peroxidase 4 (GPX4) axis, is key to eliminating lipid ROS, with GPX4 regarded as a key regulator of ferroptosis. Additionally, GPX4-independent pathways, such as the NADPH/ferroptosis suppressor protein 1 (FSP1)/coenzyme Q10 and the GTP cyclohydrolase-1/tetrahydrobiopterin/dihydrobiopterin axes, have also been implicated in the ferroptosis process in the past few years (14-16) (Fig. 1).
3. Association between ferroptosis and the immune system
Two types of immunity exist in the body, innate and adaptive. The innate immune system detects invading pathogens, while the adaptive immune system promotes a specific and long-lasting protection against infection. Innate immune cells mainly include dendritic cells, macrophages and neutrophils, while the adaptive immune system generally contains T and B lymphocytes and nature killer (NK) cells (17).
In the last few years, more evidence has revealed a close association between ferroptosis and the immune system (18,19). Notably, autoimmune disease is initiated and propagated by the activation of self-antigen-reactive T cells (20), pointing to the crucial role of T cells in autoimmunity. In a study investigating ferroptosis in immunity, both antigen-specific CD8+ and CD4+ T cells failed to expand and protect infection in T cell-specific GPX4-deficient mice (TΔGpx4/ΔGpx4), whereas GPX4-deficient T cells rapidly accumulated lipid peroxides and underwent ferroptosis in vitro (21). Ferroptosis was found to be involved in immunotherapy-activated CD8+ T cells, with increased ferroptosis contributing to the anti-tumor efficacy of immunotherapy (22). Recently, the homeostasis of follicular helper T cells, a specialized subset of CD4+ T cells, was also shown to be regulated by ferroptosis (23).
Key features of ferroptosis, iron overload and lipid peroxidation, participate in immunity. Iron overload increases oxidative stress and DNA damage in T cells, leading to immune dysfunction (24), while lipid peroxidation is associated with intracellular ROS in regulatory T cells (25). Ferroptosis affects the viability of B cells, with Muri et al (26) demonstrating that GPX4 is key to the development, maintenance and responses of B1 and marginal zone B cells via suppression of ferroptosis. Moreover, the ferroptosis inducer erastin increases lipid peroxidation and promotes peripheral blood mononuclear cell proliferation and differentiation into B and NK cells (27).
In addition to its links to the adaptive immune system, ferroptosis also plays a key role in innate immunity. In tumor cells, exogenous circularly polarized magnetic field-induced ferroptosis leads to the maturation of dendritic cells (28) and in immune-competent mice, ferroptosis promotes phenotypical maturation of bone-marrow-derived dendritic cells (29). With regard to other innate immune cells, ferroptosis is associated with the infiltration of macrophages and neutrophils (30), while also regulating polarization of macrophages (31) and the recruitment of neutrophils (32).
4. Damage-associated molecular patterns (DAMPs)
Although the pathology of autoimmune disease is complex, it is hypothesized that inflammation serves a key role in autoimmunity (33). DAMPs, endogenous molecules released by damaged tissue or dying cells, have been proved to be detrimental in inflammatory response and lead to the development of inflammatory disorders (34,35). Autoimmune diseases, such as SLE (36) and IBD (37), are among the inflammatory disorders initiated by DAMPs. In the host, DAMPs either activate innate immune cells, leading to release of various cytokines and chemokines and activation of adaptive immune responses, or stimulate adaptive immune cells directly (35).
As a key part of regulated cell death, ferroptosis can stimulate the release of DAMPs. Adenosine triphosphate (ATP) and high mobility group box 1 (HMGB1), two well-characterized DAMPs, are released along during ferroptosis in murine fibrosarcoma MCA205 or glioma GL261(29) and p53 R273H-expressing non-small cell lung cancer cells (38). Cotreatment with erastin and celastrol initiates expression of heat shock proteins (HSPs) (39). Using the immunoprecipitation assay, an interaction between HSP90 and GPX4 has been demonstrated in a model of acute kidney injury (AKI) (40). Another DAMP, calreticulin, also participates in ferroptosis. In the head and neck squamous cell carcinoma, Zhao et al (41) found ferroptosis reverses immunosuppressive microenvironments by releasing calreticulin and HMGB1, while Van Loenhout et al (42) demonstrated that auranofin and plasma-treated PBS mixture-induced ferroptosis led to a significant increase in calreticulin, ATP and HMGB1. The aforementioned reports point to a close link between ferroptosis and DAMPs, which may partly explain the mechanism of ferroptosis-mediated autoimmunity. Autoimmune diseases are also associated with cytokines and chemokines. In a mouse AKI model, ferrostatin-1 was shown to prevent upregulation of IL-33(43). Additionally, liproxstatin-1 alleviates radiation-induced lung fibrosis via the downregulation of TGF-β1(44). Ferroptosis, therefore, could have an intimate relationship with autoimmune disease.
5. Ferroptosis and autoimmune disease
Autoimmune diseases are complicated and characterized by the development of specific autoantibodies and the presence of autoreactive T cells, leading to the impairment of sustained immune responses and organs (45). Recent studies have highlighted the association between ferroptosis and autoimmune disease (Table I).
6. Ferroptosis and autoimmune hepatitis (AIH)
AIH is an immune-mediated inflammatory liver disorder characterized by histological abnormality, as well as elevated aspartate aminotransferase, alanine aminotransferase and total IgG and the presence of autoantibodies (46).
In concanavalin A (ConA)-induced hepatitis, redox-active iron accumulation and malondialdehyde (MDA) are detected in the hepatic tissues of mice. Moreover, the expression of GPX4 and system xc- is markedly decreased in the liver of ConA-treated mice and is accompanied by the downregulation of caveolin-1(47). In LO2 hepatocyte cell line, the overexpression of caveolin-1 results in the upregulation of the expression of system xc-, suggesting that cavelolin-1 protects against ConA-induced AIH by inhibiting ferroptosis. In another study, levels of cyclooxygenase2 and acyl-coenzyme A synthase long-chain family member 4 (ACSL4) were shown to be upregulated in the liver tissue of S100-induced AIH model mice, while the levels of GPX4 and ferritin heavy chain 1 (FTH1) are downregulated (48). In addition, GPX4 knockdown via adeno-associated virus injection aggravates severity of S100-induced AIH. The aforementioned studies suggested that ferroptosis is a possible mediator of AIH.
7. Ferroptosis and RA
RA is the most common autoimmune inflammatory arthritis in adults and is characterized by chronic destructive synovitis and multisystem disorder (49,50).
In the rheumatoid synovium and synovial fluid of patients with RA, the levels of iron accumulation and lipid peroxidation increase, while in a collagen-induced arthritis (CIA) mouse model, selectively targeting fibroblasts in vivo to induce ferroptosis attenuates arthritis progression, indicating that ferroptosis inducers serve as candidates for RA treatment (51). Sulfasalazine, a U.S. Food and Drug Administration-approved RA drug, is an effective inducer of ferroptosis (52). As shown by Ling et al (53), the expression of ACSL4 declines, while the expression of FTH1, GPX4, and cystine/glutamate antiporter solute carrier family 7 member 11 are increased in the RA synovium of CIA model mouse compared with healthy control (53). Luo and Zhang (54) showed that in a lipopolysaccharide-induced synovitis cell model, MDA levels are increased, whereas GPX4 levels are decreased, representing an increase in ferroptosis in human synoviocytes; inhibition of ferroptosis may be a new therapeutic strategy for synovitis (54). Further studies are required to identify the exact role of ferroptosis in RA.
8. Ferroptosis and SLE
SLE is a multisystem autoimmune disease characterized by formation of autoantibodies, deposition of immune complexes and inflammation that primarily presents in women of reproductive age. The pathogenetic mechanisms of SLE are complex and this disorder is prone to relapse and remissions, leading to considerable morbidity and mortality (55,56).
Previous studies have examined the association between iron metabolism and SLE (57-59). Li et al (60) investigated the direct association between ferroptosis and SLE; the study demonstrated ferroptosis of neutrophils in lupus-prone mice and patients with SLE and hypothesized that neutrophil ferroptosis as an essential driver of neutropenia in SLE and treatment using specific ferroptosis inhibitors may ameliorate SLE severity and symptoms (60).
9. Ferroptosis and IBD
IBD, including Crohn's disease (CD) and ulcerative colitis (UC), is a complex chronic inflammation disorder that arises due to dysregulated immune response (61). Smoking, diet, lifestyle and behavior, as well as gut microbiota, are all key contributors to disease pathogenesis (62).
Mayr et al (63) found GPX4 activity is impaired and lipid peroxidation is augmented in small intestinal epithelial cells (IECs) of patients with CD. They also found that PUFA exposure induces lipid peroxidation and cytokine production by GPX4 small-interfering RNA IECs, while the genetic deletion of ACSL4 abrogates PUFA-induced cytokine production, suggesting that inflammatory cytokine production in IECs of patients with CD is driven by ferroptotic mechanisms (63). Xu et al (64) demonstrated significantly downregulated GPX4 and notably upregulated ACSL4 expression in the colonic biopsy specimens of patients with CD. In addition, MDA content and prostaglandin-endoperoxide synthase 2 (PTGS2) levels are higher in colon samples from mice with trinitrobenzene sulfonic acid-induced colitis, pointing to a close association between ferroptosis and CD (64).
Ferroptosis has also been investigated in UC, with Xu et al (65) reporting its involvement in IEC death in UC (65). The aforementioned study found several ferroptosis-associated genes to be remarkably down- or upregulated in human colonic biopsy samples from patients with UC, while PTGS2 is elevated and GPX4 diminished in colonic IECs from experimental colitis mice. Preventing ferroptosis through inhibiting the Nrf2/heme oxygenase-1 signaling pathway may be a valuable approach to inhibit progression of UC in dextran sulfate sodium (DSS)-induced experimental colitis mice (66,67). The aforementioned findings suggested that ferroptosis is involved in IBD and could serve as a therapeutic target.
10. Ferroptosis and MS
MS is considered an autoimmune disorder of the central nervous system that is characterized by inflammation, demyelination and degeneration (68,69). mRNA levels of GPX4 in the brain of patients with MS are decreased, while the levels of GPX4 mRNA and protein are decreased and lipid peroxidation is enhanced in an experimental autoimmune encephalomyelitis mouse model (70). Jhelum et al (71) investigated the underlying mechanism of cuprizone (CZ), a copper chelator, used to induce oligodendrocyte (OL) cell loss and demyelination, revealing that CZ treatment resulted in an increase in mRNA expression of nuclear receptor coactivator 4, transferrin receptor 1 and PTGS2, as well as lipid peroxidation, and a decrease in the expression of GPX4 and system xc- in the brain tissue of experimental mice. Additionally, the CZ-induced loss of OL and demyelination was prevented by ferrostatin-1(71). These results indicated that ferroptosis is a potential therapeutic target for MS.
11. Ferroptosis and Parkinson's disease (PD)
PD is one of the most common types of neurodegenerative disorder (72) and has also been proposed as an autoimmune disease (73). Numerous studies have examined the association between ferroptosis and PD (7,74,75).
In 2016, Do Van et al (7) reported the role of ferroptosis in PD for the first time, finding ferroptosis components in PD neuropathology. Moreover, the aforementioned study found dopaminergic neuronal loss is inhibited by ferroptosis-specific inhibitors ferostatin-1 and liproxstatin-1 and that modulation of the ferroptotic signaling cascade is a possible target for drug candidates for PD. Ferroptosis occurs in the pathology of PD and they share several hallmarks, including iron overload, lipid peroxidation and decreased GSH levels (76-78). Recently, Zuo et al (79) demonstrated that paraquat, a neurotoxin that increases the risk of PD, significantly induces iron accumulation in the cytoplasm and mitochondria of SH-SY5Y human neuroblastoma cells via the ferritinophagy pathway; however, ferritinophagy-mediated ferroptosis is significantly ameliorated by ferrostatin-1, pointing to the inhibition of ferroptosis as a potential new strategy for the prevention of neurotoxicity or PD (79). Reagents targeting ferroptosis could be used in the treatment of PD in the future.
12. Ferroptosis and psoriasis
Psoriasis is a chronic immune-mediated inflammatory skin disease characterized by hyperproliferation of keratinocytes and excessive infiltration of immune cells. Currently, it is considered a systemic disease associated with metabolic, arthritic and cardiovascular comorbidities (80).
A previous study showed a significant reduction in GPX4 and elevation in Nrf2 downstream targets in psoriatic skin lesions compared with samples from healthy patients (81). Additionally, the mRNA levels of ACSL4, PTGS2 and TFR are much higher in psoriasis lesions than in healthy controls. Furthermore, in an imiquimod (IMQ)-induced mouse model of psoriasis, immunohistochemical analysis uncovered notably increased ACSL4 levels and markedly decreased GPX4 levels in the basal epidermal layer and ferrostatin-1 treatment attenuated IMQ-induced psoriasis-like dermatitis (82). Ferroptosis is, therefore, a potential physiological mechanism for eliminating inflammatory response in psoriasis.
13. Ferroptosis and IDDM
IDDM is a chronic disorder stemming from autoimmune damage of pancreatic β cells (83). While ferroptosis is involved in cell death of the myocardium and renal tubules during diabetes (84-87), the role of ferroptosis in the death of β cells is unknown. In 2018, Bruni et al reported massive ferroptosis in pancreatic islets isolated from IDDM patients, whereas the transplantable number of islet equivalents increased following addition of ferrostatin (88). Along with evidence that ferroptosis is induced in rat pancreatic β cells after exposure to tert-butyl hydroperoxide (89), ferroptosis can be considered a possible mode of β cell destruction. However, more studies are required to determine the link between ferroptosis and β cell death.
14. Ferroptosis as a therapeutic target for autoimmune disease
As aforementioned, there is an association between ferroptosis and autoimmune disease. Therefore, targeting ferroptosis is a promising therapeutic option for autoimmune disease. Ferroptosis can primarily be inhibited by iron chelators and lipophilic antioxidants (1). The present review summarizes anti-ferroptosis agents and their potential benefits in the treatment of autoimmune disorder (Table II).
15. Iron chelators
Deferoxamine (DFO) has been investigated in the treatment of several types of autoimmune disease. In patients with RA, DFO prevents synovial injury (90) and improves anemia (91). A pilot study showed that patients with MS tolerate a short course of DFO therapy relatively well (92), however, no effect on disease progression has been noted (93). In addition to its effect against RA and MS, DFO has been found to ameliorate motor defects and pathology in a PD rat model (94). Deferiprone (DFP), another iron chelator, suppresses disease activity in a mouse model of MS (95). Additionally, DFP reportedly improves motor performance of patients with PD in a phase II clinical trial (96). DFP can ameliorate DSS-induced UC in a mouse model by suppressing ferroptosis (67). The aforementioned studies indicate that iron chelators are promising therapeutic options for autoimmune disease. However, larger clinal trials are needed to determine the value of iron chelators in the therapy of autoimmune disease.
16. Lipophilic antioxidants
Ferrostatin-1 and liproxstatin-1 are well-known inhibitors of ferroptosis. Numerous studies have investigated these ferroptosis inhibitors in autoimmune diseases, including AIH, IBD and PD (48,97). To the best of our knowledge, however, examinations have yet to be conducted in models other than experimental mouse models. Hence, clinical trials must be performed to explore their roles in patients.
Vitamin E is a key lipid soluble antioxidant that can suppress ferroptosis by inhibiting 15-lipoxygenase (98). Reports show that supplementation with vitamin E relieves joint pain in patients with RA (99). In patients with SLE, vitamin E is said to suppress autoantibody production. Moreover, vitamin E improves functional capacity and gait parameters in patients with relapsing-remitting MS (100) and improves clinical signs and metabolic status in patients with PD (101). Furthermore, supplementation with vitamin E is a feasible option for the management of patients with severe forms of psoriasis as it decreases the markers of oxidative stress (102). Vitamin E treatment, therefore, may be a therapeutic option for autoimmune diseases.
Selenium, an essential trace element with antioxidant properties, has been assessed as a potential treatment for autoimmune diseases. Supplementation with selenium relieves inflammatory reaction in patients with MS (103), IBD (104) and psoriasis (102). However, it has shown no significant clinical benefit against RA (105,106). In preclinical studies, selenium decreases loss of dopamine and slows the progression of neurodegeneration during PD (107).
N-acetylcysteine, a pharmaceutical drug with an anti-ferroptosis property, has been investigated in the treatment of RA and SLE. In patients with RA, the oral administration of N-acetylcysteine relieves severity of joint pain and improves physical performance (108). In patients with SLE, N-acetylcysteine inhibits lupus disease activity (109).
Polyphenols are natural antioxidants that prevent ferroptosis owing to their ROS scavenging property (110). Resveratrol, a well-studied polyphenol, decreases disease activity score assessment for 28 joints in patients with RA (111), decreases the clinical colitis activity index score and improves quality of life in patients with UC (112,113) and exerts antidiabetic and antioxidant effects in patients with IDDM (114). Other polyphenols, such as pomegranate juice could alleviate disease activity of patients with RA (115), and licorice could improve symptoms in patients with PD (116).
Although the aforementioned experiments posited lipophilic antioxidants as having potential role in the therapy of autoimmune disease, larger and more in-depth studies are required to determine the exact impact of various polyphenols in the treatment of autoimmune disorder.
17. Conclusion
The present review summarized research on ferroptosis in autoimmune disorders and discussed ferroptosis as a promising therapeutic target. Although autoimmune diseases are heterogeneous in manifestation, there are commonalities between these disorders with respect to ferroptosis. Among these key commonalities is inflammation (117,118). As an important part of regulated cell death, ferroptosis stimulates release of DAMPs and inflammatory cytokines, leading to activation of immune response and eventually promoting the development of autoimmune disease.
Recently, the role of ferroptosis in autoimmune diseases has been reviewed. Fan et al (11) highlighted crosstalk between ferroptosis and different immune cells and discussed the role of ferroptosis in autoimmune disease and Lai et al (10) also discussed how ferroptosis contributes to the pathogenesis of SLE, RA and IBD. However, the autoimmune diseases included in the aforementioned reviews are relatively limited and did not summarize the association between ferroptosis and autoimmune response. Hence, the present review is more comprehensive and may provide more information about the association between ferroptosis and autoimmune disease.
Even though recent evaluations have investigated ferroptosis in autoimmune disorders, the association between this cell death type and autoimmune diseases is relatively undeveloped. Therefore, more studies are required to determine the association between ferroptosis and autoimmune disease, including Graves' disease, Hashimoto thyroiditis, coeliac disease, Addison disease and autoimmune myocarditis and polyendocrine syndrome type 2. Additionally, although numerous ferroptosis-related reagents have been investigated in the treatment of various autoimmune diseases, the reported efficacy pertains mainly to basic studies, patient sample sizes and follow-up periods were relatively limited. Hence, larger clinical trials must be performed to highlight and confirm the treatment values of ferroptosis-associated regents.
In summary, ferroptosis plays a critical role in the pathogenesis of autoimmune diseases and is a promising therapeutic target for autoimmune diseases.
Acknowledgements
Figures were produced by Figdraw (www.figdraw.com), we express our gratitude.
Funding
Funding: The present study was supported by the Zhejiang Provincial Science Foundation of China (grant no. LGF21H020006), the Pioneer Innovation Team of Jiaxing Institute of Atherosclerotic Diseases (grant no. XFCX-DMYH), Program of the First Hospital of Jiaxing (grant no. 2021-YA-001), the Jiaxing Key Laboratory of Arteriosclerotic Diseases (grant no. 2020-dmzdsys) and Jiaxing Key Laboratory of Virus-mediated Infectious Diseases (grant no. 2021-bdzdsys).
Availability of data and materials
Not applicable.
Authors' contributions
LS and XW drafted the manuscript. CZ edited the manuscript. YC designed the study and revised the manuscript. All authors have read and approved the final 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.
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