Oxidized mitochondrial DNA induces gasdermin D oligomerization in systemic lupus erythematosus

• Published in: Nature communications Vol. 14; no. 1; p. 872
• Main Authors: Miao, Naijun, Wang, Zhuning, Wang, Qinlan, Xie, Hongyan, Yang, Ninghao, Wang, Yanzhe, Wang, Jin, Kang, Haixia, Bai, Wenjuan, Wang, Yuanyuan, He, Rui, Yan, Kepeng, Wang, Yang, Hu, Qiongyi, Liu, Zhaoyuan, Li, Fubin, Wang, Feng, Ginhoux, Florent, Zhang, Xiaoling, Yin, Jianyong, Lu, Limin, Wang, Jing
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.02.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 14/19; 14/34; 14/69; 38/109; 38/91; 631/250/1933; 631/250/2504/223/1699; 631/80/86/2366; 64/110; 64/60; 96/106; 96/21; 96/31; Animals; Antibodies; Antigen-antibody complexes; Antigens; Apoptosis; Arginine deiminase; Autoantibodies; Autoimmune diseases; Caspase 1 - metabolism; Caspase-1; Caspase-11; Cell death; Chronic conditions; Disulfiram; DNA, Mitochondrial - metabolism; Gasdermins; Humanities and Social Sciences; Humans; Leukocytes (granulocytic); Leukocytes (neutrophilic); Lupus; Lupus Erythematosus, Systemic; Mice; Mitochondrial DNA; multidisciplinary; Neutrophils; Oligomerization; Phosphate-Binding Proteins - metabolism; Pore formation; Pristane; Protein Multimerization; Protein-arginine deiminase; Science; Science (multidisciplinary); Serpins - metabolism; Stimulation; Systemic lupus erythematosus; Therapeutic targets; γ-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-36522-z

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. Systemic lupus erythematosus is characterised by the generation of antibodies targeting DNA and nuclear antigens. Here, the authors show that oxidised mitochondrial DNA induces gasdermin D oligomerization and promotes pore formation in neutrophils from patients with SLE.