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
Purpose: Echinacoside (ECH) has been reported to have anti-inflammatory and anti-immune effects, and may be effective for treating asthma. This study aimed to investigate the effect of ECH on asthma. Methods: A mouse model of asthma was established by ovalbumin (OVA) induction, and the effect of ECH on airway remodeling in mice was evaluated using the Periodic Acid-Schiff stain and enzyme-linked immunosorbent serologic assay (ELISA). Additionally, the effect of ECH on collagen deposition in asthmatic mice was assessed using Western blotting (WB) analysis, and response to airway inflammation was evaluated by ELISA. The signaling pathway regulated by ECH was also investigated using WB. Results: Our findings demonstrated that ECH restored OVA-induced increase in mucin, immunoglobulin E, and respiratory resistance. ECH also alleviated OVA-induced collagen deposition, including collagen I, collagen III, alpha smooth muscle actin, and epithelial (E)-cadherin. Moreover, ECH restored the elevated levels of interleukin (IL)-13, IL-17, and the increased number of macrophages, eosinophils, lymphocytes, and neutrophills induced by OVA. ECH mainly exerted its regulatory effects by modulating the silent mating type information regulation 2 homolog 1 (Sirtuin 1/SIRT1)–nuclear factor kappa B (NF-κB) signaling pathway in the mouse models of asthma. Conclusion: This study highlights the therapeutic potential of ECH for attenuating airway remodeling and inflammation in an OVA-induced neonatal mouse model of asthma through the modulation of SIRT1/NF-κB pathway.
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