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

• Published in: Immunity (Cambridge, Mass.) Vol. 51; no. 6; pp. 983 - 996.e6
• Main Authors: Yang, Xinyu, Cheng, Xiaoye, Tang, Yiting, Qiu, Xianhui, Wang, Yupeng, Kang, Haixia, Wu, Jianfeng, Wang, Zhongtai, Liu, Yukun, Chen, Fangping, Xiao, Xianzhong, Mackman, Nigel, Billiar, Timothy R., Han, Jiahuai, Lu, Ben
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.12.2019; Elsevier Limited
• Subjects: Ablation; Animals; Apoptosis; Bacteria; Bacterial infections; Biomarkers; Blood Coagulation - physiology; Blood platelets; Calcium; Calcium influx; Caspase-11; Caspases, Initiator - genetics; Caspases, Initiator - metabolism; Cell activation; Cell death; Cell Line, Tumor; Clonal deletion; Coagulation; Disseminated intravascular coagulation; Disseminated Intravascular Coagulation - pathology; Endotoxemia - pathology; Endotoxins; Enzyme Activation; Exposure; Gram-negative bacteria; HeLa Cells; HT29 Cells; Humans; IL-1β; Infections; Interleukin-1alpha - blood; Interleukin-1beta - blood; Interleukins; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Leukocytes; Lipopolysaccharides; Lipopolysaccharides - metabolism; Liver; Mice; Mice, Inbred C57BL; Mice, Knockout; Mortality; Neutralization; non-canonical inflammasome; Phosphate-Binding Proteins - genetics; Phosphate-Binding Proteins - metabolism; Phosphatidylserine; phosphatidylserine exposure; Phosphatidylserines - metabolism; Phospholipids; Pores; Proteins; Pyroptosis - physiology; Rodents; Sepsis; Signal Transduction - physiology; Thromboplastin - metabolism; Tissue factor; caspase-11; non-canonical inflammasome; phosphatidylserine exposure; coagulation; sepsis
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2019.11.005

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. [Display omitted] •Deletion of caspase-11 prevents disseminated intravascular coagulation (DIC) in sepsis•Deletion of GSDMD prevents caspase-11- and TF-mediated DIC in endotoxemia•GSDMD deficiency inhibits endotoxin-induced TF activation by reducing PS exposure•Activation of GSDMD by caspase-11 triggers Ca2+-dependent PS exposure through TMEM16F Excessive activation of the coagulation system by endotoxin leads to life-threatening disseminated intravascular coagulation (DIC). Yang, Cheng et al. reveal that caspase-11, a cytosolic LPS receptor, activates the coagulation cascade by enhancing the activation of tissue factor, an initiator of coagulation, through triggering the formation of gasdermin (GASMD) pores and subsequent phosphatidylserine exposure, in a manner independent of cell death.