Ferroptosis and Autoimmune Diseases

Abstract

Adequate control of autoimmune diseases with an unclear etiology resulting from autoreactivation of the immune system remains a major challenge. One of the factors that trigger autoimmunity is the abnormal induction of cell death and the inadequate clearance of dead cells that leads to the exposure or release of intracellular contents that activate the immune system. Different from other cell death subtypes, such as apoptosis, necroptosis, autophagy, and pyroptosis, ferroptosis has a unique association with the cellular iron load (but not the loads of other metals) and preserves its distinguishable morphological, biological, and genetic features. This review addresses how ferroptosis is initiated and how it contributes to the pathogenesis of autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel diseases. The mechanisms responsible for ferroptosis-associated events are discussed. We also cover the perspective of targeting ferroptosis as a potential therapeutic for patients with autoimmune diseases. Collectively, this review provides up-to-date knowledge regarding how ferroptosis occurs and its significance in autoimmune diseases.

Keywords: ferroptosis; inflammation; inflammatory bowel diseases; rheumatoid arthritis; systemic lupus erythematosus.

Figure 1

Initiation and mechanisms regulating ferroptosis. Several key factors, including cystine uptake, levels of GSH, and activities of Gpx4, act as crucial regulators counteracting iron-dependent generation of lipid peroxidation products and preventing ferroptosis and plasma membrane damage. One molecule of cystine across plasma membrane with an exchange of one molecule of glutamate through cystine-glutamate antiporter (System Xc^-). Inside the cell, cystine is reduced to cysteine for GSH synthesis. GSH is easily oxidized to the disulfide dimer GSSG (oxidized form of glutathione). Extracellular iron can be transported to intracellular through transferring protein 1. Iron as an electron carrier also functions as a redox catalyst in the Fenton and Haber-Weiss reactions resulting in the generation of ROS. Mitochondria are critical organelle containing ferroptosis-related genes and regulate generation of lipid peroxides through the electron-transporting chain. Ferroptotic pathway can be initiated by activation of cytokines such as IFN-α, IFN-γ and IL-6 or serum IgG (e.g. in SLE patients) leading to the activation of CaMKIV/CREMα axis as an example demonstrated in SLE. Binding of CREMα to Gpx4 promoter resulted in suppression of Gpx4 expression which regulates biosynthesis of GSH. Gpx4 also catalyzes the reduction of oxidized biolipids, that converts toxic lipid hydroperoxides into non-toxic lipid alcohols through its cofactor GSH. Dysregulation of these factors leads to ferroptosis with release of damage-associated molecular patterns like HMGB1 and membrane rupture. GSH, glutathione; GPX4, glutathione peroxidase 4; CaMKIV, Ca²⁺/calmodulin–dependent kinase IV; CREMα, cAMP-responsive element modulator α; IFN-α, interferon-alpha; IFN-γ, interferon-gamma; IL-6, interleukin-6; HMGB1, high mobility group box 1; OXPHOS, oxidative phosphorylation.

Figure 2

Ferroptosis of synovial fibroblasts in RA and its association with disease activity. Oxidative stress resulted in increased production of ROS, induced proliferation of synovial fibroblasts and caused synovitis and joint destruction in patients with RA. In synovial space, infiltrating macrophages produced proinflammatory cytokines such as TNF-α and IL-6, both are critical in mediating RA pathogenesis. However, TNF-α and IL-6 have different roles in regulating ferroptosis. TNF-α provided survival signal for fibroblast activation protein-α (FAP)α+ fibroblasts in synovial areas close to infiltrating macrophages, exaggerated synovial inflammation and increased RA disease activity. This was done by activating or inducing several regulators associated with GSH biosynthesis, including SLC7A11, GSH, NF-κB, GCLC, GCLM and reducing ACSL4 in ferroptosis-resistant FAPα+ fibroblasts. In contrast, IL-6 increased intracellular iron levels, decreased the expression of SLC40A1 and ferritin and resulted in inducing ferroptosis of synovial fibroblasts. Auranofin differential regulated ferroptosis depending on the dosages of administration. IKE and Gpx4 inhibitor RSL3 treatment induced ferroptosis, downregulated numbers of FAPα+ fibroblasts and reduced severity of synovitis. TNF-α, tuor necrosis factor alpha; IL-6, interleukin-6; FAP, fibroblast activation protein; Gpx4, glutathione peroxidase 4; SLC7A11, solute carrier family 7 member 11; GSH, glutathione; GCLC, a glutamate-cysteine ligase regulatory subunit; GCLM, a glutamate-cysteine ligase catalytic subunit; SLC40A1, solute carrier family 40 member 1; IKE, imidazole ketone erastin; RSL3, RAS synthetic lethal 3.

Figure 3

Ferroptosis of intestinal epithelial cells in IBD. Over-supplementation of iron caused its deposition in the intestine and led to excessive production of ROS and intestinal inflammation (red IEC). AA, EPA and DHA listed here are part of PUFAs. PUFAs whose uptake is mediated by CD36 are the major substrates for lipid peroxidation. The oxidation of PUFAs can be regulated by either lipoxygenase-mediated reaction, or Fenton-type reaction, in the plasma membrane. ACSL4 that esterifies AA into phospholipids facilitated peroxidation. Oxidation of PUFAs induced pro-inflammatory cytokines or mediators like IL-6, CXCL1 production in IEC as well as lipid peroxidation and ferroptosis of IECs. The expression and enzymatic activity of Gpx4 prevents lipid peroxidation in IEC (green IEC). The ER stress was also shown to be mediating IEC ferroptosis and suppression of ER stress with GSK2606414 inhibited ferroptosis of IECs. CD, Crohn’s disease; UC, ulcerative colitis; IEC, intestinal epithelial cell; PUFAs, polyunsaturated fatty acids; AA: arachidonic acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; GSH, glutathione; Gpx4, glutathione peroxidase 4; ACSL4, acyl coenzyme A synthetase long chain 4; ER, endoplasmic reticulum; IL-6, interleukin-6; CXCL1, chemokine (C-X-C motif) ligand 1.