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

Research output: Contribution to journalArticle

  • Laura C Burzynski
  • Melanie Humphry
  • Katerina Pyrillou
  • Kimberley A Wiggins
  • Julie N E Chan
  • Nichola Figg
  • Lauren L Kitt
  • Charlotte Summers
  • Kate C Tatham
  • Paul B Martin
  • Martin R Bennett
  • Murray C H Clarke
Original languageEnglish
Pages (from-to)1033-1042.e6
Number of pages17
JournalImmunity
Volume50
Issue number4
Early online date26 Mar 2019
DOIs
DateAccepted/In press - 27 Feb 2019
DateE-pub ahead of print - 26 Mar 2019
DatePublished (current) - 16 Apr 2019

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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Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

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