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

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

  • Redox Biol. 2023 Dec 20:69:103008. doi: 10.1016/j.redox.2023.103008.
Yan Liu 1,  Xiqing Luo 2,  Ye Chen 1,  Junlong Dang 3,  Donglan Zeng 4,  Xinghua Guo 2,  Weizhen Weng 2,  Jun Zhao 4,  Xiaoyi Shi 1,  Jingrong Chen 1,  Bo Dong 2,  Shuyuan Zhong 2,  Jianhua Ren 5,  Yuhang Li 5,  Julie Wang 6,  Jingwen Zhang 7,  Jianbo Sun 8,  Hanshi Xu 9,  Yan Lu 4,  David Brand 10,  Song Guo Zheng 11,  Yunfeng Pan 12
Affiliations

Affiliations

  • 1 Department of Rheumatology and Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China; Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
  • 2 Department of Rheumatology and Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
  • 3 Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China.
  • 4 Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
  • 5 Department of Joint and Trauma Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
  • 6 Division of Rheumatology and Immunology, Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Songjiang District Central Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 7 Department of Hematology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
  • 8 Department of Clinical Research, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China.
  • 9 Department of Rheumatology and Immunology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
  • 10 The Lt. Col. Luke Weathers, Jr. VA Medical Center, Memphis, TN, 38163, United States.
  • 11 Division of Rheumatology and Immunology, Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Songjiang District Central Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. Electronic address: Song.Zheng@shsmu.edu.cn.
  • 12 Department of Rheumatology and Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China. Electronic address: panyunf@mail.sysu.edu.cn.
PMID: 38142586 DOI: 10.1016/j.redox.2023.103008
Abstract

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.

Keywords

Ferroptosis; GPX4; Iron overload; Macrophage; Rheumatoid arthritis.

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