Bacterial outer membrane vesicles induce disseminated intravascular coagulation through the caspase-11-gasdermin D pathway. Issue 196 (December 2020)

• Record Type: Journal Article
• Authors: Peng, Yue; Gao, Min; Liu, Yukun; Qiu, Xianhui; Cheng, Xiaoye; Yang, Xinyu; Chen, Fangping; Wang, Erhua
• Is Part Of: Thrombosis research. Issue 196(2020)
• Page Start: 159
• Page End: 166
• Publication Date: 2020-12
• Subjects: Disseminated intravascular coagulation -- Outer membrane vesicles -- Caspase-11 -- GSDMD; Thrombosis -- Periodicals; 616.135
• DOI: 10.1016/j.thromres.2020.08.013
• Languages: English
• ISSNs: 0049-3848

Abstract

Abstract: Background: Disseminated intravascular coagulation (DIC), a severe complication of sepsis, promotes multiple organ dysfunctions and lethality. Bacterial infection is the most common cause of sepsis. We previously show an important role of bacteria-released outer membrane vesicles (OMVs) in bacterial infection-induced DIC. In the light of recent advance that activation of caspase-11 and its enzymatic substrate gasdermin D (GSDMD) is able to trigger coagulation, we postulate that OMVs might induce DIC through the caspase-11-GSDMD pathway. Methods: Caspase-11- or GSDMD-deficient mice and their wild-type (WT) controls were injected with purified Escherichia coli -derived OMVs. Blood samples were then collected. The development of DIC was assessed in terms of the occurrence of coagulopathy, the organ injuries and the lethality. Peritoneal macrophages derived from WT, Caspase-11- or GSDMD-deficient mice were stimulated with OMVs. Then the cell surface tissue factor (TF) activity and thrombin generation were assessed. Results: Genetic deletion of Caspase-11 or GSDMD or pharmacological inhibition of caspase-11 markedly attenuated OMVs-induced coagulopathy, multiple organ injuries and mortality. Caspase-11- or GSDMD-deficient macrophages exhibited markedly reduced TF activity after OMVs stimulation. Conclusion: OMVs induce DIC through the caspase-11-GSDMD pathway. These findings might open a new avenue to prevent or treat bacterial infection-induced DIC. Highlights: Caspase-11 and gasdermin D mediate OMVs-induced DIC. OMVs induce DIC independent of the IL-1 signaling. Caspase-11 and GSDMD mediate OMVs-induced DIC by increasing TF activity.