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

摘要

class="head no_bottom_margin" id="sec1title">IntroductionWith the emergence of multicellular life came a greater need to protect against invasion by pathogens and thus the rapid evolution of the immune system. The coagulation system developed from an early innate immune system, with blood serine proteases diverging from complement-like proteases (). Bleeding is the primary challenge to survival after wounding, followed by the risk of infection. Thus, activation of inflammation during hemostasis is likely advantageous. Ancient organisms such as horseshoe crabs utilize a combined coagulation and immune system where clotting plugs wounds and entraps pathogens (). Although links between coagulation and immunity exist in mammals, they are indirect and slower to act.Coagulation acts immediately, with the intrinsic or extrinsic pathway activating a protease cascade that drives rapid thrombin activation, fibrin deposition, and platelet activation, leading to hemostasis. Innate immunity is slower and typically requires sensing of pathogen-associated molecular patterns to activate apical cytokines, such as interleukin-1 (IL-1), to direct inflammation and subsequent adaptive immunity (). Inflammation induces tissue factor to promote coagulation, while thrombin induces inflammation via cleavage of protease-activated receptors (PARs) (). These slower kinetics could allow microbes to proliferate within, for example, a wound. Hence, a quicker and more direct link between hemostasis and immunity in mammals would benefit host fitness.IL-1 is ancient with IL-1 homologues identified in echinoderms (). IL-1 signaling via the type 1 IL-1 receptor (IL-1R1) leads to multiple inflammatory effects including vasodilation, increased vascular permeability (), cytokine secretion, leucocyte recruitment, and upregulation of major histocompatibility complex and co-stimulatory molecules (). IL-1 also effects adaptive immunity by enhancing Th17 differentiation and effector T cell proliferation with Tregs present (, ). These potent effects mean that IL-1 activity is tightly controlled at multiple levels, including a receptor antagonist (IL-1RA), a decoy receptor (IL-1R2), and expression of IL-1α (, ) and IL-1β () as proproteins that require proteolysis for full activity. While IL-1β is activated by complex multimeric inflammasomes, IL-1α is cleaved by calpain () or granzyme B (). Importantly, increased IL-1 activity is a hallmark of many chronic inflammatory conditions, including rheumatoid arthritis, diabetes, and atherosclerosis.We identified a direct link between the coagulation and immune systems. IL-1α was activated by thrombin cleavage at a highly conserved site, implying functional importance. We showed key roles for thrombin-cleaved IL-1α in rapid thrombopoiesis after acute platelet loss and for wound healing. We also identified thrombin-cleaved IL-1α in humans with sepsis-associated adult respiratory distress syndrome (ARDS). These findings will likely have widespread implications for inflammatory and thrombotic diseases and normal physiology.