TMEM173 Drives Lethal Coagulation in Sepsis
TMEM173 Drives Lethal Coagulation in Sepsis
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TMEM173 驱动脓毒症中的致命凝血
DOI：
10.1016/j.chom.2020.02.004
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发表时间：
2020-04-08
影响因子：
30.3
通讯作者：
Tang, Daolin
中科院分区：
文献类型：
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作者：
Zhang, Hui;Zeng, Ling;Tang, Daolin
TMEM 173/STING依赖性先天免疫的发现最近为炎症性疾病的预防和管理提供了指导。在这里，我们表明，髓样TMEM 173通过一种独立于I型干扰素反应的机制在调节细菌感染的凝血中发挥重要作用。从机制上讲，TMEM 173与ITPR 1的结合控制了巨噬细胞和单核细胞中内质网的钙释放。细胞溶质钙的TMEM 173依赖性增加驱动Gasdermin D（GSDMD）裂解和活化，其触发F3的释放，F3是血液凝固的关键引发剂。TMEM 173-GSDMD-F3途径的遗传或药理学抑制阻断了全身凝血，并改善了三种脓毒症模型（盲肠结扎和穿孔或大肠杆菌或肺炎链球菌感染的菌血症）中的动物存活率。TMEM 173通路的上调与脓毒症患者弥散性血管内凝血的严重程度和死亡率相关。因此，TMEM 173是致命细菌感染期间血液凝固的关键调节剂。
The discovery of TMEM173/STING-dependent innate immunity has recently provided guidance for the prevention and management of inflammatory disorders. Here, we show that myeloid TMEM173 occupies an essential role in regulating coagulation in bacterial infections through a mechanism independent of type I interferon response. Mechanistically, TMEM173 binding to ITPR1 controls calcium release from the endoplasmic reticulum in macrophages and monocytes. The TMEM173-dependent increase in cytosolic calcium drives Gasdermin D (GSDMD) cleavage and activation, which triggers the release of F3, the key initiator of blood coagulation. Genetic or pharmacological inhibition of the TMEM173-GSDMD-F3 pathway blocks systemic coagulation and improves animal survival in three models of sepsis (cecal ligation and puncture or bacteremia with Escherichia coli or Streptococcus pneumoniae infection). The upregulation of the TMEM173 pathway correlates with the severity of disseminated intravascular coagulation and mortality in patients with sepsis. Thus, TMEM173 is a key regulator of blood clotting during lethal bacterial infections.