呂奔團隊破譯細菌內毒素激活凝血級聯機制
作者：
小柯機器人發布時間：2019/12/17 15:43:56
近日，中南大學湘雅三醫院呂奔課題組發現，細菌內毒素通過Gasdermin D依賴的磷脂醯絲氨酸暴露激活凝血級聯。 該研究於2019年12月10日在線發表於國際一流學術期刊《免疫》。
研究人員檢查了脂多糖（LPS）激活凝血的基礎機制，LPS是革蘭氏陰性細菌的主要細胞壁成分。研究人員發現，胞漿LPS受體caspase-11激活了凝血級聯反應。caspase-11以與細胞死亡無關的方式，通過觸發GSDMD（gasdermin D）孔的形成和隨後的磷脂醯絲氨酸的暴露，增強了凝血的起始因子組織因子（TF）的活化。GSDMD孔介導了鈣內流，從而通過跨膜蛋白16F（一種鈣依賴性磷脂稀疏酶）誘導了磷脂醯絲氨酸的暴露。Casp11的敲除、Gsdmd的減少、磷脂醯絲氨酸或TF的中和阻止了LPS誘導的彌散性血管內凝血（DIC）。在敗血病患者中，血清白介素（IL）-1α和IL-1β（GSSDD活化的生物標誌物）的濃度與外周血白細胞中磷脂醯絲氨酸的暴露和DIC評分相關。這些發現將LPS的免疫識別與凝結機制聯繫起來，對DIC的治療有一定影響。
據了解，凝血系統的過度激活導致危及生命的DIC。
附：英文原文
Title: Bacterial Endotoxin Activates the Coagulation Cascade through Gasdermin D-Dependent Phosphatidylserine Exposure
Author: Xinyu Yang, Xiaoye Cheng, Yiting Tang, Xianhui Qiu, Yupeng Wang, Haixia Kang, Jianfeng Wu, Zhongtai Wang, Yukun Liu, Fangping Chen, Xianzhong Xiao, Nigel Mackman, Timothy R. Billiar, Jiahuai Han, Ben Lu
Issue&Volume: December 10, 2019
Abstract: Excessive activation of the coagulation system leads to life-threatening disseminatedintravascular coagulation (DIC). Here, we examined the mechanisms underlying the activationof coagulation by lipopolysaccharide (LPS), the major cell-wall component of Gram-negativebacteria. We found that caspase-11, a cytosolic LPS receptor, activated the coagulationcascade. Caspase-11 enhanced the activation of tissue factor (TF), an initiator ofcoagulation, through triggering the formation of gasdermin D (GSDMD) pores and subsequentphosphatidylserine exposure, in a manner independent of cell death. GSDMD pores mediatedcalcium influx, which induced phosphatidylserine exposure through transmembrane protein16F, a calcium-dependent phospholipid scramblase. Deletion of Casp11, ablation of Gsdmd, or neutralization of phosphatidylserine or TF prevented LPS-induced DIC. In septicpatients, plasma concentrations of interleukin (IL)-1α and IL-1β, biomarkers of GSDMDactivation, correlated with phosphatidylserine exposure in peripheral leukocytes andDIC scores. Our findings mechanistically link immune recognition of LPS to coagulation,with implications for the treatment of DIC.
DOI: 10.1016/j.immuni.2019.11.005
Source: https://www.cell.com/immunity/fulltext/S1074-7613(19)30463-7