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.

中文翻译：

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TMEM173驱动败血症中的致死性凝血。

TMEM173 / STING依赖性先天免疫的发现最近为预防和控制炎症提供了指导。在这里，我们表明髓样TMEM173通过独立于I型干扰素反应的机制，在调节细菌感染中的凝血中起着至关重要的作用。从机理上讲，与ITPR1结合的TMEM173控制着钙从巨噬细胞和单核细胞中的内质网释放。TMEM173依赖于胞质钙的增加会驱动Gasdermin D（GSDMD）裂解和激活，从而触发F3（凝血的主要引发剂）的释放。TMEM173-GSDMD-F3途径的遗传或药理抑制作用可阻断全身性凝结，并改善败血症的三种模型（盲肠结扎，穿刺或细菌血症或大肠埃希菌或肺炎链球菌感染）的动物存活率。TMEM173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，TMEM173是致死性细菌感染过程中血液凝结的关键调节剂。