The Coagulation and Immune Systems Are Directly Linked through the Activation of Interleukin-1α by Thrombin

Ancient organisms have a combined coagulation and immune system, and although links between inflammation and hemostasis exist in mammals, they are indirect and slower to act. Here we investigated direct links between mammalian immune and coagulation systems by examining cytokine proproteins for potential thrombin protease consensus sites. We found that interleukin (IL)-1 alpha is directly activated by thrombin. Thrombin cleaved pro-IL-1 alpha at a site perfectly conserved across disparate species, indicating functional importance. Surface pro-IL-1 alpha on macrophages and activated platelets was cleaved and activated by thrombin, while tissue factor, a potent thrombin activator, colocalized with pro-IL1 alpha in the epidermis. Mice bearing a mutation in the IL-1 alpha thrombin cleavage site (R114Q) exhibited defects in efficient wound healing and rapid thrombopoiesis after acute platelet loss. Thrombin-cleaved IL-1 alpha was detected in humans during sepsis, pointing to the relevance of this pathway for normal physiology and the pathogenesis of inflammatory and thrombotic diseases.