Oxidized mitochondrial DNA induces gasdermin D oligomerization in systemic lupus erythematosus

Oxidized mitochondrial DNA induces gasdermin D oligomerization in systemic lupus erythematosus

Nature Communications

10.1038/s41467-023-36522-z

https://doi.org/10.1038/s41467-023-36522-z

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, Jing Wang

16 February 2023

Miao, N., Wang, Z., Wang, Q., Xie, H., Yang, N., Wang, Y., Wang, J., Kang, H., Bai, W., Wang, Y., He, R., Yan, K., Wang, Y., Hu, Q., Liu, Z., Li, F., Wang, F., Ginhoux, F., Zhang, X., … Wang, J. (2023). Oxidized mitochondrial DNA induces gasdermin D oligomerization in systemic lupus erythematosus. Nature Communications, 14(1). https://doi.org/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.

Attribution 4.0 International (CC BY 4.0)

This research is supported by core funding from: A*STAR Singapore Immunology Network (A*STAR SIgN)
Grant Reference no. :

https://oar.a-star.edu.sg/communities-collections/articles/22530

2041-1723

Singapore Immunology Network

https://doi.org/10.1038/s41467-023-36522-z