Bacterial infection not only stimulates innate immune responses but also activates coagulation cascades. Overactivation of the coagulation system in bacterial sepsis leads to disseminated intravascular coagulation (DIC), a life-threatening condition. However, the mechanisms by which bacterial infection activates the coagulation cascade are not fully understood. Here we show that type 1 interferons (IFNs), a widely expressed family of cytokines that orchestrate innate antiviral and antibacterial immunity, mediate bacterial infection-induced DIC by amplifying the release of high-mobility group box 1 (HMGB1) into the bloodstream. Inhibition of the expression of type 1 IFNs and disruption of their receptor IFN-α/βR or downstream effector (eg, HMGB1) uniformly decreased gram-negative bacteria-induced DIC. Mechanistically, extracellular HMGB1 markedly increased the procoagulant activity of tissue factor by promoting the externalization of phosphatidylserine to the outer cell surface, where phosphatidylserine assembles a complex of cofactor-proteases of the coagulation cascades. These findings not only provide novel insights into the link between innate immune responses and coagulation, but they also open a new avenue for developing novel therapeutic strategies to prevent DIC in sepsis.

中文翻译：

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1 型干扰素在革兰氏阴性菌诱导凝血中的作用

细菌感染不仅会刺激先天免疫反应，还会激活凝血级联反应。细菌性败血症中凝血系统的过度激活会导致弥散性血管内凝血 (DIC)，这是一种危及生命的疾病。然而，细菌感染激活凝血级联反应的机制尚不完全清楚。在这里，我们展示了 1 型干扰素 (IFN)，一种广泛表达的细胞因子家族，可协调先天抗病毒和抗菌免疫，通过放大高迁移率族框 1 (HMGB1) 释放到血液中来介导细菌感染诱导的 DIC。抑制 1 型 IFN 的表达并破坏其受体 IFN-α/βR 或下游效应器（例如，HMGB1）均会降低革兰氏阴性菌诱导的 DIC。从机制上讲，细胞外 HMGB1 通过促进磷脂酰丝氨酸外化到细胞外表面，显着增加了组织因子的促凝活性，其中磷脂酰丝氨酸组装了凝血级联的辅因子 - 蛋白酶复合物。这些发现不仅为先天免疫反应和凝血之间的联系提供了新的见解，而且还为开发新的治疗策略以预防败血症中的 DIC 开辟了新的途径。