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Immunity. 2019 Apr 16;50(4):1033-1042.e6. doi: 10.1016/j.immuni.2019.03.003. Epub 2019 Mar 26.

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

Author information

1
Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
2
Division of Anaesthesia, Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
3
Section of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, SW7 2AZ, UK.
4
School of Biochemistry, Biomedical Sciences, University of Bristol, Bristol, BS8 1TD, UK.
5
Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK. Electronic address: mchc2@cam.ac.uk.

Abstract

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)-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.

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