Heterogeneous ferroptosis susceptibility of macrophages caused by focal iron overload exacerbates rheumatoid arthritis

Focal iron overload is frequently observed in patients with rheumatoid arthritis (RA), yet its functional significance remains elusive. Herein, we report that iron deposition in lesion aggravates arthritis by inducing macrophage ferroptosis. We show that excessive iron in synovial fluid positively c...

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Veröffentlicht in:Redox biology 2024-02, Vol.69, p.103008, Article 103008
Hauptverfasser: Liu, Yan, Luo, Xiqing, Chen, Ye, Dang, Junlong, Zeng, Donglan, Guo, Xinghua, Weng, Weizhen, Zhao, Jun, Shi, Xiaoyi, Chen, Jingrong, Dong, Bo, Zhong, Shuyuan, Ren, Jianhua, Li, Yuhang, Wang, Julie, Zhang, Jingwen, Sun, Jianbo, Xu, Hanshi, Lu, Yan, Brand, David, Zheng, Song Guo, Pan, Yunfeng
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Sprache:eng
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Zusammenfassung:Focal iron overload is frequently observed in patients with rheumatoid arthritis (RA), yet its functional significance remains elusive. Herein, we report that iron deposition in lesion aggravates arthritis by inducing macrophage ferroptosis. We show that excessive iron in synovial fluid positively correlates with RA disease severity as does lipid hyperoxidation of focal monocyte/macrophages. Further study reveals high susceptibility to iron induced ferroptosis of the anti-inflammatory macrophages M2, while pro-inflammatory M1 are less affected. Distinct glutathione peroxidase 4 (GPX4) degradation depending on p62/SQSTM1 in the two cell types make great contribution mechanically. Of note, ferroptosis inhibitor liproxstatin-1 (LPX-1) can alleviate the progression of K/BxN serum-transfer induced arthritis (STIA) mice accompanied with increasing M2 macrophages proportion. We thus propose that the heterogeneous ferroptosis susceptibility of macrophage subtypes as well as consequent inflammation and immune disorders are potential biomarkers and therapeutic targets in RA. [Display omitted] •Focal iron overload is a distinct feature of the rheumatoid arthritis (RA) joint microenvironment.•Ferroptosis, a form of regulated cell death, is closely associated with iron level.•In the presence of excess iron in the joint, M2 macrophages are more susceptible to ferroptosis than M1.•Autophagic degradation of GPX4 in macrophages subtypes made great contribution to heterogeneous ferroptosis susceptibility.
ISSN:2213-2317
2213-2317
DOI:10.1016/j.redox.2023.103008