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

Laura C Burzynski,Charlotte Summers,Murray C.H Clarke,Lauren L Kitt,Julie N.E Chan,Kate C Tatham,Nichola Figg,Katerina Pyrillou,Kimberley A Wiggins,Martin R Bennett,Paul B Martin,Melanie Humphry

doi:10.1016/j.immuni.2019.03.003

Laura C Burzynski, Charlotte Summers + Show 10 more

Open Access

https://doi.org/10.1016/j.immuni.2019.03.003

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Abstract

SummaryAncient 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)-1α is directly activated by thrombin. Thrombin cleaved pro-IL-1α at a site perfectly conserved across disparate species, indicating functional importance. Surface pro-IL-1α on macrophages and activated platelets was cleaved and activated by thrombin, while tissue factor, a potent thrombin activator, colocalized with pro-IL-1α in the epidermis. Mice bearing a mutation in the IL-1α thrombin cleavage site (R114Q) exhibited defects in efficient wound healing and rapid thrombopoiesis after acute platelet loss. Thrombin-cleaved IL-1α was detected in humans during sepsis, pointing to the relevance of this pathway for normal physiology and the pathogenesis of inflammatory and thrombotic diseases.

Highlights

With the emergence of multicellular life came a greater need to protect against invasion by pathogens and the rapid evolution of the immune system
We identified a direct link between the coagulation and immune systems
We identified thrombin-cleaved IL-1a in humans with sepsis-associated adult respiratory distress syndrome (ARDS)

Summary

Introduction

With the emergence of multicellular life came a greater need to protect against invasion by pathogens and 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 (Delvaeye and Conway, 2009). Bleeding is the primary challenge to survival after wounding, followed by the risk of infection. 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 (Delvaeye and Conway, 2009). Links between coagulation and immunity exist in mammals, they are indirect and slower to act

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