Abstract 038: Inflammasome Activation Triggers Blood Coagulation Through Pyroptosis
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Background: Disseminated intravascular coagulation (DIC) is a frequent and fatal complication of sepsis. The presence of bacterial virulence factors can induce blood coagulation, yet the molecular events linking bacteria sensing to initiation of the coagulation cascade remain largely unknown. Inflammasome is the large sensory protein complex in the cytosol that alerts host to bacterial infection. The role of inflammasome in sepsis remains unclear.
Methods and Results: We used E. coli type III secretion system (T3SS) inner rod protein EprJ and LPS to investigate the role of canonical and noncanonical inflammasome activation in sepsis, respectively. For efficient cytosolic delivery, EprJ was fused to the cytosolic translocation domain of anthrax lethal factor (LFn). Binding with LFn, anthrax protein protective agent (PA) delivers the LFn-EprJ fusion protein into the cytoplasma through receptor-mediated endocytosis. We found that EprJ, the inner rod protein, activated caspase-1 and induced systemic coagulation, while lipopolysaccharide (LPS) produced similar effects via caspase-11 activation. We also identified gasdermin D (Gsdmd) driven macrophage pyroptosis as a mechanism for the release of tissue factor, an essential initiator of coagulation cascades. Genetic deficiency of Gsdmd abolishes inflammasome-mediated coagulation.
Conclusion: Inflammasome activation is a trigger for coagulation induced by Gram-negative bacterial products, connecting inflammation and thrombosis.
Arteriosclerosis Thrombosis and Vascular Biology
author list (cited authors)
Wu, C., Wei, Y., & Li, Z.
complete list of authors
Wu, Congqing||Wei, Yinan||Li, Zhenyu