Inflammasome Activation Triggers Blood Clotting and Host Death through Pyroptosis

Congqing Wu, Wei Lu, Yan Zhang, Guoying Zhang, Xuyan Shi, Yohei Hisada, Steven P. Grover, Xinyi Zhang, Lan Li, Binggang Xiang, Jumei Shi, Xiang An Li, Alan Daugherty, Susan S. Smyth, Daniel Kirchhofer, Toshihiko Shiroishi, Feng Shao, Nigel Mackman, Yinan Wei, Zhenyu Li

Research output: Contribution to journalArticlepeer-review

243 Scopus citations

Abstract

Inflammasome activation and subsequent pyroptosis are critical defense mechanisms against microbes. However, overactivation of inflammasome leads to death of the host. Although recent studies have uncovered the mechanism of pyroptosis following inflammasome activation, how pyroptotic cell death drives pathogenesis, eventually leading to death of the host, is unknown. Here, we identified inflammasome activation as a trigger for blood clotting through pyroptosis. We have shown that canonical inflammasome activation by the conserved type III secretion system (T3SS) rod proteins from Gram-negative bacteria or noncanonical inflammasome activation by lipopolysaccharide (LPS) induced systemic blood clotting and massive thrombosis in tissues. Following inflammasome activation, pyroptotic macrophages released tissue factor (TF), an essential initiator of coagulation cascades. Genetic or pharmacological inhibition of TF abolishes inflammasome-mediated blood clotting and protects against death. Our data reveal that blood clotting is the major cause of host death following inflammasome activation and demonstrate that inflammasome bridges inflammation with thrombosis. Overactivation of inflammasome leads to death of the host. Wu and colleagues demonstrate that activation of coagulation is responsible for inflammasome activation-induced death.

Original languageEnglish
Pages (from-to)1401-1411.e4
JournalImmunity
Volume50
Issue number6
DOIs
StatePublished - Jun 18 2019

Bibliographical note

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

  • DIC
  • GSDMD
  • LPS
  • caspase
  • coagulation
  • inflammasome
  • macrophage
  • pyroptosis
  • sepsis
  • tissue factor

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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