Bacterial Endotoxin Activates Coagulation Cascades Through GSDMD-Dependent Phosphatidylserine Exposure

Abstract

Excessive activation of the coagulation system by endotoxin (lipopolysaccharide: LPS), the major cell-wall component of Gram-negative bacteria, leads to life-threatening disseminated intravascular coagulation (DIC). However, the underlying mechanisms remain largely unknown. Here, we show that caspase-11, a cytosolic LPS receptor, activates the coagulation cascade through gasdermin D (GSDMD) and tissue factor (TF), an initiator of coagulation cascades. Upon activation by caspase-11, GSDMD-mediated phosphatidylserine exposure markedly enhances the activation of TF. Genetic deletion or pharmacological inhibition of caspase-11, ablation of GSDMD or neutralization of phosphatidylserine or TF uniformly prevents LPS-induced DIC. Further, plasma concentrations of interleukin (IL)-1α and IL-1β, biomarkers of GSDMD activation, correlated with phosphatidylserine exposure in peripheral leukocytes and DIC scores in septic patients. These findings not only identify molecular links between innate immunity and coagulation, but also could open a new avenue to prevent infection-induced DIC.