Gasdermin D-dependent platelet pyroptosis exacerbates NET formation and inflammation in severe sepsis

Su, Meiling and Chen, Chaofei and Li, Shaoying and Li, Musheng and Zeng, Zhi and Zhang, Yuan and Xia, Luoxing and Li, Xiuzhen and Zheng, Dezhong and Lin, Qiqi and Fan, Xuejiao and Wen, Ying and Liu, Yingying and Chen, Feiyan and Luo, Wei and Bu, Yun and Qin, Jinhong and Guo, Manli and Qiu, Miaoyun and Sun, Lei and Liu, Renjing and Wang, Ping and Hwa, John and Tang, Wai Ho (2022) Gasdermin D-dependent platelet pyroptosis exacerbates NET formation and inflammation in severe sepsis. Nature Cardiovascular Research, 1 (8). pp.732-747. ISSN 2731-0590

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Platelets have emerged as key inflammatory cells implicated in the pathology of sepsis, but their contributions to rapid clinical deterioration and dysregulated inflammation have not been defined. Here, we show that the incidence of thrombocytopathy and inflammatory cytokine release was significantly increased in patients with severe sepsis. Platelet proteomic analysis revealed significant upregulation of gasdermin D (GSDMD). Using platelet-specific Gsdmd-deficient mice, we demonstrated a requirement for GSDMD in triggering platelet pyroptosis in cecal ligation and puncture (CLP)-induced sepsis. GSDMD-dependent platelet pyroptosis was induced by high levels of S100A8/A9 targeting toll-like receptor 4 (TLR4). Pyroptotic platelet-derived oxidized mitochondrial DNA (ox-mtDNA) potentially promoted neutrophil extracellular trap (NET) formation, which contributed to platelet pyroptosis by releasing S100A8/A9, forming a positive feedback loop that led to the excessive release of inflammatory cytokines. Both pharmacological inhibition using Paquinimod and genetic ablation of the S100A8/A9-TLR4 signaling axis improved survival in mice with CLP-induced sepsis by suppressing platelet pyroptosis.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 03 Mar 2023 01:09
Last Modified: 03 Mar 2023 01:09

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