Yue Peng1, Min Gao1, Yukun Liu2, Xianhui Qiu2, Xiaoye Cheng2, Xinyu Yang2, Fangping Chen2, Erhua Wang3. 1. Department of Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, PR China. 2. Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, PR China. 3. Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, PR China. Electronic address: ehwang@csu.edu.cn.
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.
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-deficientmice 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-deficientmice 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.
Authors: Kari Lavinia Vom Werth; Theresa Wörmann; Björn Kemper; Philipp Kümpers; Stefanie Kampmeier; Alexander Mellmann Journal: Microorganisms Date: 2022-02-08