Abstract
BackgroundReactive oxygen species accumulation and iron overload are involved in the pathogenesis of rheumatoid arthritis (RA). Ferroptosis, as a non-apoptotic form of programmed cell death, characteristically depends on iron and lipid peroxidation. However, the role of ferroptosis in RA has not been explored.ObjectivesTo explore the role of ferroptosis in immune imbalance of rheumatoid arthritis.MethodsIron content in synovial fluid was determined by colorimetry. Lipid peroxidation was assessed by flow cytometry and immunofluorescence. MDA and GSH were used as markers to assess iferroptosis. K/BxN spontaneous arthritis mice and serum-induced arthritis mice were used as in vivo animal models of ferroptosis.ResultsIron overload and hyperlipid peroxidation of mononuclear-macrophages were found in the synovial fluid of RA patients. Liproxstatin-1, the specific inhibitor of ferroptosis, alleviated the progression of arthritis mice model by increasing M2-like macrophage numbers. Mechanistically, iron overload in arthritis lesion induced anti-inflammatory macrophage ferroptosis by promoting glutathione peroxidase 4 (GPX4, a classical anti-ferroptosis molecule) to undergo P62 - dependent autophagy degradation.ConclusionOur results provide compelling evidence that macrophages ferroptosis plays a major role in RA. M2-like macrophages are more sensitive to ferroptosis than M1-like macrophages under iron overload circulation. This finding heavily contributes to the immune imbalance of rheumatoid arthritis.References[1]Xin Chen, et al. Cellular degradation systems in ferroptosis. Cell Death & Differentiation, (2021) 28:1135–1148.[2]Pengchong Li,et al. Glutathione peroxidase 4-regulated neutrophil ferroptosis induces systemic autoimmunity. Nat Immunol, 2021 Sep;22(9):1107-1117.[3]Alexandr A Kapralov, et al. Redox lipid reprogramming commands susceptibility of macrophages and microglia to ferroptotic death. Nat Chem Biol, 2020 Mar;16(3):278-290.Disclosure of InterestsYan Liu Grant/research support from: the National Natural Science Foundation of China (82101899), China Postdoctoral Science Foundation Grant (2021M693658), Yutong Jiang Grant/research support from: Basic and Applied Basic Research Fund Project of Guandong Province [2021A1515111172], yunfeng pan: None declared
Subject
General Biochemistry, Genetics and Molecular Biology,Immunology,Immunology and Allergy,Rheumatology