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

Immunity. 2019 Dec 17;51(6):983-996.e6. doi: 10.1016/j.immuni.2019.11.005. Epub 2019 Dec 10.


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.

Keywords: caspase-11; coagulation; non-canonical inflammasome; phosphatidylserine exposure; sepsis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Coagulation / physiology
  • Caspases, Initiator / genetics
  • Caspases, Initiator / metabolism*
  • Cell Line, Tumor
  • Disseminated Intravascular Coagulation / pathology*
  • Endotoxemia / pathology
  • Enzyme Activation
  • HT29 Cells
  • HeLa Cells
  • Humans
  • Interleukin-1alpha / blood
  • Interleukin-1beta / blood
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lipopolysaccharides / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphate-Binding Proteins / genetics
  • Phosphate-Binding Proteins / metabolism*
  • Phosphatidylserines / metabolism*
  • Pyroptosis / physiology
  • Signal Transduction / physiology
  • Thromboplastin / metabolism*


  • Gsdmd protein, mouse
  • IL1A protein, human
  • IL1B protein, human
  • Interleukin-1alpha
  • Interleukin-1beta
  • Intracellular Signaling Peptides and Proteins
  • Lipopolysaccharides
  • Phosphate-Binding Proteins
  • Phosphatidylserines
  • Thromboplastin
  • Casp4 protein, mouse
  • Caspases, Initiator