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Bacterial outer membrane vesicles induce disseminated intravascular coagulation through the caspase-11-gasdermin D
Yue Peng1, Min Gao1, Yukun Liu2
1Department of Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, PR China.
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.
Insights
Outer membrane vesicles (OMVs) from bacteria trigger disseminated intravascular coagulation (DIC) via the caspase-11-gasdermin D pathway. This discovery offers new strategies for treating sepsis-induced DIC.
Area of Science:
- Infectious Diseases
- Hematology
- Immunology
Background:
- Disseminated intravascular coagulation (DIC) is a severe sepsis complication leading to organ dysfunction and death.
- Bacterial infections are a primary cause of sepsis.
- Bacteria-derived outer membrane vesicles (OMVs) play a role in sepsis-induced DIC.
Purpose of the Study:
- To investigate the role of the caspase-11-gasdermin D (GSDMD) pathway in OMVs-induced DIC.
- To determine if OMVs trigger DIC through this specific molecular pathway.
Main Methods:
- Wild-type and deficient mice (caspase-11 or GSDMD) were injected with purified Escherichia coli OMVs.
- DIC development was assessed via coagulopathy, organ injury, and mortality.
- Macrophage tissue factor activity and thrombin generation were measured after OMV stimulation.
Main Results:
- Genetic deletion or pharmacological inhibition of caspase-11 or GSDMD significantly reduced OMV-induced coagulopathy, organ injury, and mortality.
- Macrophages deficient in caspase-11 or GSDMD showed reduced tissue factor activity upon OMV stimulation.
Conclusions:
- OMVs induce DIC by activating the caspase-11-GSDMD pathway.
- These findings suggest potential new therapeutic targets for bacterial infection-induced DIC.
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