2. Academic Validation
  3. Gasdermin D-dependent platelet pyroptosis exacerbates NET formation and inflammation in severe sepsis

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

  • Nat Cardiovasc Res. 2022;1(8):732-747. doi: 10.1038/s44161-022-00108-7.
Meiling Su # 1,  Chaofei Chen # 1 2 3,  Shaoying Li 1,  Musheng Li 1,  Zhi Zeng 1,  Yuan Zhang 1,  Luoxing Xia 1,  Xiuzhen Li 1,  Dezhong Zheng 4,  Qiqi Lin 1,  Xuejiao Fan 1,  Ying Wen 1,  Yingying Liu 1,  Feiyan Chen 1,  Wei Luo 1,  Yun Bu 1,  Jinhong Qin 1,  Manli Guo 1,  Miaoyun Qiu 1,  Lei Sun 1,  Renjing Liu 5,  Ping Wang # 1,  John Hwa # 6,  Wai Ho Tang # 1 7
Affiliations

Affiliations

  • 1 Institute of Pediatrics, Guangzhou Women and Children's Medical Centre, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, China.
  • 2 The Joint Center for Infection and Immunity, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou, China.
  • 3 The Joint Center for Infection and Immunity, Institute Pasteur of Shanghai, Chinese Academy of Science, Shanghai, China.
  • 4 Department of Cardiology, Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou, China.
  • 5 Victor Chang Cardiac Research Institute, Sydney, Australia.
  • 6 Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, CT USA.
  • 7 School of Nursing and Health Studies, Hong Kong Metropolitan University, Kowloon, Hong Kong SAR China.
  • # Contributed equally.
PMID: 35967457 DOI: 10.1038/s44161-022-00108-7
Abstract

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.

Keywords

Cell death; Cell death and immune response; Inflammation; Innate immunity.

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