Disulfiram alleviates pristane-induced lupus via inhibiting GSDMD-mediated pyroptosis

• Published in: Cell death discovery 2022-09, Vol.8 (1), p.379-379, Article 379
• Main Authors: Zhuang, Lili, Luo, Xiaoqing, Wu, Shufan, Lin, Zhangmei, Zhang, Yanan, Zhai, Zeqing, Yang, Fangyuan, Li, Yehao, Zhuang, Jian, Luo, Guihu, Xu, Wenchao, He, Yi, Sun, Erwei
• Format: Article
• Language: English
• Subjects: 692/420/256/2177; 692/699/249/1313/1613/1614; Anti-DNA antibodies; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Cell death; Disulfiram; Gene expression; IL-1β; Inflammasomes; Inflammation; Leukocytes (mononuclear); Life Sciences; Lupus; Macrophages; Monocytes; Pathogenesis; Patients; Peripheral blood mononuclear cells; Pristane; Proteinuria; Pyroptosis; Stem Cells; Systemic lupus erythematosus
• ISSN: 2058-7716; 2058-7716
• DOI: 10.1038/s41420-022-01167-2

Activation of multiple inflammasomes in monocytes/macrophages is associated with the pathogenesis of systemic lupus erythematosus (SLE). Gasdermin D (GSDMD)-mediated pyroptosis, a common consequence of multiple activated inflammasomes, is a programmed cell death with strong inflammatory responses. This suggested that targeting monocyte/macrophage pyroptosis might provide an opportunity to cure SLE. Here, we aimed to investigate the effect of disulfiram (DSF), a small molecule inhibitor of pyroptosis, and its potential therapeutic mechanism for SLE. The mRNA expression of GSDMD and IL-1β were significantly increased in peripheral blood mononuclear cells (PBMCs) from SLE patients. Importantly, we found serum from SLE patients rather than healthy controls induced GSDMD-mediated pyroptosis in THP-1 cells, as evidenced by enhanced LDH release, increased number of PI-positive cells, and high expression of full-length GSDMD and N-terminal GSDMD. Interestingly, treatment with DSF obviously inhibited pyroptosis of THP-1 cells induced by serum from SLE patients. Of note, DSF administration reduced proteinuria, serum anti-dsDNA level, and renal immune complex. It also attenuated renal damage in PIL mice. Further research found that the high level of serum IL-β and GSDMD-mediated pyroptosis of glomerular macrophages in PIL mice were rescued with DSF treatment. These data implied that GSDMD-mediated monocytes/macrophages pyroptosis played an important role in the pathogenesis of SLE and DSF might be a potential alternative therapeutic agent for SLE.