Oxidized mitochondrial DNA induces gasdermin D oligomerization in systemic lupus erythematosus

Naijun Miao, Zhuning Wang, Qinlan Wang, Hongyan Xie, Ninghao Yang, Yanzhe Wang, Jin Wang, Haixia Kang, Wenjuan Bai, Yuanyuan Wang, Rui He, Kepeng Yan, Yang Wang, Qiongyi Hu, Zhaoyuan Liu, Fubin Li, Feng Wang, Florent Ginhoux, Xiaoling Zhang, Jianyong Yin (), Limin Lu () and Jing Wang ()
Additional contact information
Naijun Miao: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Zhuning Wang: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Qinlan Wang: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Hongyan Xie: Fudan University
Ninghao Yang: Fudan University
Yanzhe Wang: Shanghai Jiao Tong University School of Medicine
Jin Wang: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Haixia Kang: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Wenjuan Bai: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Yuanyuan Wang: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Rui He: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Kepeng Yan: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Yang Wang: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Qiongyi Hu: Shanghai Jiao Tong University School of Medicine
Zhaoyuan Liu: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Fubin Li: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Feng Wang: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Florent Ginhoux: Singapore Immunology Network, Agency for Science, Technology and Research
Xiaoling Zhang: Shanghai Jiao Tong University School of Medicine
Jianyong Yin: Shanghai Jiao Tong University Affiliated Sixth People’s Hospital
Limin Lu: Fudan University
Jing Wang: Ruijin Hospital, Shanghai Jiao Tong University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: Abstract Although extracellular DNA is known to form immune complexes (ICs) with autoantibodies in systemic lupus erythematosus (SLE), the mechanisms leading to the release of DNA from cells remain poorly characterized. Here, we show that the pore-forming protein, gasdermin D (GSDMD), is required for nuclear DNA and mitochondrial DNA (mtDNA) release from neutrophils and lytic cell death following ex vivo stimulation with serum from patients with SLE and IFN-γ. Mechanistically, the activation of FcγR downregulated Serpinb1 following ex vivo stimulation with serum from patients with SLE, leading to spontaneous activation of both caspase-1/caspase-11 and cleavage of GSDMD into GSDMD-N. Furthermore, mtDNA oxidization promoted GSDMD-N oligomerization and cell death. In addition, GSDMD, but not peptidyl arginine deiminase 4 is necessary for extracellular mtDNA release from low-density granulocytes from SLE patients or healthy human neutrophils following incubation with ICs. Using the pristane-induced lupus model, we show that disease severity is significantly reduced in mice with neutrophil-specific Gsdmd deficiency or following treatment with the GSDMD inhibitor, disulfiram. Altogether, our study highlights an important role for oxidized mtDNA in inducing GSDMD oligomerization and pore formation. These findings also suggest that GSDMD might represent a possible therapeutic target in SLE.

Date: 2023
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DOI: 10.1038/s41467-023-36522-z

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