Department of Hematology and Critical Care Medicine, The 3rd Xiangya Hospital, Central South University, Changsha 410000, P.R. China.
Department of Physiology, School of Basic Medical Science, Central South University, Changsha, Hunan Province 410000, P.R. China.
Immunity. 2019 Dec 17;51(6):983-996.e6. doi: 10.1016/j.immuni.2019.11.005. Epub 2019 Dec 10.
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.
凝血系统的过度激活可导致危及生命的弥漫性血管内凝血（DIC）。在这里，我们研究了脂多糖（LPS）激活凝血的机制，LPS 是革兰氏阴性菌细胞壁的主要成分。我们发现，胞质 LPS 受体胱天蛋白酶-11（caspase-11）激活了凝血级联反应。胱天蛋白酶-11 通过触发 gasdermin D（GSDMD）孔的形成和随后的磷脂酰丝氨酸暴露，在不依赖细胞死亡的情况下增强组织因子（TF）的激活，TF 是凝血的起始因子。GSDMD 孔介导钙内流，通过跨膜蛋白 16F 诱导磷脂酰丝氨酸暴露，16F 是一种钙依赖性磷脂翻转酶。Casp11 缺失、Gsdmd 消融或磷脂酰丝氨酸或 TF 中和可防止 LPS 诱导的 DIC。在脓毒症患者中，白细胞介素（IL）-1α 和 IL-1β 的血浆浓度，IL-1β 是 GSDMD 激活的生物标志物，与外周白细胞的磷脂酰丝氨酸暴露和 DIC 评分相关。我们的研究结果从机制上把 LPS 的免疫识别与凝血联系起来，这对 DIC 的治疗有影响。
