2. Academic Validation
  3. Oxidized mitochondrial DNA induces gasdermin D oligomerization in systemic lupus erythematosus

Oxidized mitochondrial DNA induces gasdermin D oligomerization in systemic lupus erythematosus

  • Nat Commun. 2023 Feb 16;14(1):872. doi: 10.1038/s41467-023-36522-z.
Naijun Miao # 1,  Zhuning Wang # 1,  Qinlan Wang 1,  Hongyan Xie 2,  Ninghao Yang 2,  Yanzhe Wang 3,  Jin Wang 1,  Haixia Kang 1,  Wenjuan Bai 1,  Yuanyuan Wang 1,  Rui He 1,  Kepeng Yan 1,  Yang Wang 1,  Qiongyi Hu 4,  Zhaoyuan Liu 1,  Fubin Li 1,  Feng Wang 1,  Florent Ginhoux 5,  Xiaoling Zhang 6,  Jianyong Yin 7,  Limin Lu 8,  Jing Wang 9
Affiliations

Affiliations

  • 1 Center for Immune-related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Department of Physiology and Pathophysiology, School of Basic Medicine Sciences, Fudan University, Shanghai, China.
  • 3 Department of Nephrology, Shanghai Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 4 Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 5 Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, Singapore.
  • 6 Department of Orthopedic Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 7 Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China. yinjianyong09@163.com.
  • 8 Department of Physiology and Pathophysiology, School of Basic Medicine Sciences, Fudan University, Shanghai, China. lulimin@shmu.edu.cn.
  • 9 Center for Immune-related Diseases at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. jingwang@shsmu.edu.cn.
  • # Contributed equally.
PMID: 36797275 DOI: 10.1038/s41467-023-36522-z
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.

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