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


ABSTRACT: 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.

SUBMITTER: Zhuang L 

PROVIDER: S-EPMC9440918 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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

Zhuang Lili L   Luo Xiaoqing X   Wu Shufan S   Lin Zhangmei Z   Zhang Yanan Y   Zhai Zeqing Z   Yang Fangyuan F   Li Yehao Y   Zhuang Jian J   Luo Guihu G   Xu Wenchao W   He Yi Y   Sun Erwei E  

Cell death discovery 20220903 1


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 pyropt  ...[more]

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