Bacterial infection not only stimulates innate immune responses but also activates the coagulation cascades. Over-activation 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), widely expressed family of cytokines that orchestrate innate antiviral and antibacterial immunity, mediate bacterial infection-induced DIC through amplifying the release of high mobility box group box 1 (HMGB1) into the blood stream. Inhibition of the expression of type 1 IFNs, disruption of their receptor IFN-α/βR or downstream effector (e.g., HMGB1) uniformly decreased Gram-negative bacteria-induced DIC. Mechanistically, extracellular HMGB1 markedly increased the pro-coagulant activity of tissue factor (TF) by promoting the externalization of phosphatidylserine (PS) to the outer cell surface, where PS 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 also open a new avenue for developing novel therapeutic strategies to prevent DIC in sepsis.
The role of type 1 interferons in Gram-negative bacteria-induced coagulation