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.

中文翻译：

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细菌内毒素通过加德明D依赖的磷脂酰丝氨酸暴露激活凝血级联反应。

凝血系统的过度激活会导致危及生命的弥散性血管内凝血（DIC）。在这里，我们检查了脂多糖（LPS）激活凝血的基础机制，脂多糖是革兰氏阴性细菌的主要细胞壁成分。我们发现，胞浆LPS受体caspase-11激活了凝血级联反应。Caspase-11以与细胞死亡无关的方式，通过触发胃泌素D（GSDMD）孔的形成和随后的磷脂酰丝氨酸暴露，增强了凝血因子组织因子（TF）的活化。GSDMD毛孔介导了钙内流，该钙内流通过跨膜蛋白16F（一种钙依赖性磷脂稀疏酶）诱导了磷脂酰丝氨酸的暴露。删除Casp11，消融Gsdmd，或磷脂酰丝氨酸或TF的中和阻止了LPS诱导的DIC。在败血病患者中，血浆白介素（IL）-1α和IL-1β的浓度是GSDMD激活的生物标志物，与外周血白细胞中磷脂酰丝氨酸的暴露和DIC评分相关。我们的发现将LPS的免疫识别与凝血机制性地联系起来，对DIC的治疗产生了影响。