ACSL4 inhibition prevents macrophage ferroptosis and alleviates fibrosis in bleomycin-induced systemic sclerosis model

Arthritis Research & Therapy

Research

Jina Zheng¹  Dianyu Cao¹  Qiang Wang¹  Zengrui Chen²  Yong Yu³  Zheng Li⁴ 

[1] Department of Dermatology, Zhongshan Hospital, Fudan University, No.180 Fenglin Road, Xuhui District, 200032, Shanghai, P.R. China;Department of Intensive Care Medicine, Yuhuan People’s Hospital, No. 18 Changle Road, Yucheng Street, 317600, Yuhuan City, Zhejiang, P.R. China;Key Laboratory of Viral Heart Diseases, Ministry of Public Health, Zhongshan Hospital, Fudan University, 200032, Shanghai, P.R. China;Laboratory Animal Division, Institute of Clinical Science, Zhongshan Hospital, Fudan University, 180 Fenglin Road, 200032, Shanghai, P.R. China;

关键词: Ferroptosis;    ACSL4;    Macrophage;    Fibrosis;    Calpain;    Systemic sclerosis;   

DOI  :  10.1186/s13075-023-03190-9

 received in 2023-07-25, accepted in 2023-10-10,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundSystemic sclerosis (SSc), with unclear pathophysiology, is a paradigmatic rheumatic disease of immunity dysfunction-driven multi-organ inflammation and ultimate fibrosis. Pathogenesis breakthroughs are urgently needed for available treatments halting its unremitting stiffness. This study aims to investigate whether ferroptosis can regulate the progressive SSc fibrosis.MethodsIn vivo, bleomycin (BLM)-induced mice model was subjected to ferroptosis detection using western blotting, malondialdehyde (MDA), and glutathione (GSH) assays. Pharmacological inhibitor of the acyl-CoA synthetase long-chain family member 4 (ACSL4) was utilized to explore its potential therapeutic effects for fibrosis, from histological, biochemical, and molecular analyses. In vitro, bone marrow-derived macrophages (BMDM) were activated into inflammatory phenotype and then the relationship was evaluated between activation level and ferroptosis sensitivity in lipopolysaccharide (LPS) incubation with gradient concentrations. The potential calpain/ACSL4 axis was analyzed after calpain knockdown or over-expression in Raw264.7.ResultsBoth skin and lung tissue ferroptosis were present in SSc mice with enhanced ACSL4 expression, while ACSL4 inhibition effectively halted fibrosis progressing and provides protection from inflammatory milieu. Meanwhile, a positive regulation relationship between LPS-induced macrophage activity and ferroptosis sensitivity can be observed. After calpain knockdown, both inflammatory macrophage ferroptosis sensitivity and ACSL4 expression decreased, while its over-expression renders ACSL4-envoking condition. Also, calpain pharmacological inhibition reduced both ferroptosis and fibrosis aptitude in mice.ConclusionsACSL4 induces inflammatory macrophage ferroptosis to aggravate fibrosis progressing. ACSL4 and its upregulators of calpains may be potential therapeutic targets for BLM model of SSc.

【 授权许可】

CC BY   
© The Author(s) 2023

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