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

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.

• Authors: 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
• Journal: Blood (Blood) Vol. 135 Issue 14 Pg. 1087-1100 (04 02 2020) ISSN: 1528-0020 [Electronic] United States
• PMID: 32016282 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 by The American Society of Hematology.

Chemical References

• Adaptor Proteins, Vesicular Transport
• HMGB1 Protein
• Interferon-alpha
• TICAM-1 protein, mouse
• Interferon-beta

Topics

• Adaptor Proteins, Vesicular Transport (immunology)
• Animals
• Blood Coagulation
• Disseminated Intravascular Coagulation (blood, etiology, immunology)
• Endotoxemia (blood, complications, immunology)
• Gram-Negative Bacteria (immunology)
• Gram-Negative Bacterial Infections (blood, complications, immunology)
• HMGB1 Protein (blood, immunology)
• Humans
• Immunity, Innate
• Interferon-alpha (immunology)
• Interferon-beta (immunology)
• Mice, Inbred C57BL