The role of type 1 interferons in coagulation induced by gram-negative bacteria

Xinyu Yang, Xiaoye Cheng, Yiting Tang, Xianhui Qiu, Zhongtai Wang, Guang Fu, Jianfeng Wu, Haixia Kang, Jing Wang, Haichao Wang, Fangping Chen, Xianzhong Xiao, Timothy R. Billiar, Ben Lu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

72 Scopus citations

Abstract

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. Key Points: • Type 1 IFN signaling is critical for the development of DIC in endotoxemia and bacterial sepsis. • Type 1 IFN signaling mediates the release of HMGB1, which promotes DIC by inducing phosphatidylserine exposure.

Original languageEnglish
Pages (from-to)1087-1100
Number of pages14
JournalBlood
Volume135
Issue number14
DOIs
StatePublished - 2 Apr 2020
Externally publishedYes

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