Bacterial Endotoxin Activates the Coagulation Cascade through Gasdermin D-Dependent Phosphatidylserine Exposure

Xinyu Yang, Xiaoye Cheng, Yiting Tang, Xianhui Qiu, Yupeng Wang, Haixia Kang, Jianfeng Wu, Zhongtai Wang, Yukun Liu, Fangping Chen, Xianzhong Xiao, Nigel Mackman, Timothy R. Billiar, Jiahuai Han, Ben Lu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

190 Scopus citations

Abstract

Excessive activation of the coagulation system leads to life-threatening disseminated intravascular coagulation (DIC). Here, we examined the mechanisms underlying the activation of coagulation by lipopolysaccharide (LPS), the major cell-wall component of Gram-negative bacteria. We found that caspase-11, a cytosolic LPS receptor, activated the coagulation cascade. Caspase-11 enhanced the activation of tissue factor (TF), an initiator of coagulation, through triggering the formation of gasdermin D (GSDMD) pores and subsequent phosphatidylserine exposure, in a manner independent of cell death. GSDMD pores mediated calcium influx, which induced phosphatidylserine exposure through transmembrane protein 16F, a calcium-dependent phospholipid scramblase. Deletion of Casp11, ablation of Gsdmd, or neutralization of phosphatidylserine or TF prevented LPS-induced DIC. In septic patients, plasma concentrations of interleukin (IL)-1α and IL-1β, biomarkers of GSDMD activation, correlated with phosphatidylserine exposure in peripheral leukocytes and DIC scores. Our findings mechanistically link immune recognition of LPS to coagulation, with implications for the treatment of DIC.

Original languageEnglish
Pages (from-to)983-996.e6
JournalImmunity
Volume51
Issue number6
DOIs
StatePublished - 17 Dec 2019
Externally publishedYes

Keywords

  • caspase-11
  • coagulation
  • non-canonical inflammasome
  • phosphatidylserine exposure
  • sepsis

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