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Thrombin-activated interleukin-1α drives atherogenesis, but also promotes vascular smooth muscle cell proliferation

Laura C Burzynski1, Alejandra Morales-Maldonado1, Amanda Rodgers1

  • 1Section of CardioRespiratory Medicine, The Heart and Lung Research Institute, The University of Cambridge, Papworth Road, Cambridge Biomedical Campus, Cambridge CB2 0BB, UK.

Cardiovascular Research
|June 13, 2023
PubMed

Insights

Ongoing coagulation contributes to atherosclerosis through thrombin activating interleukin-1 alpha (IL-1α). Targeting IL-1α or thrombin may offer therapeutic benefits for cardiovascular disease.

Area of Science:

  • Cardiovascular Biology
  • Immunology
  • Hematology

Background:

  • Atherosclerosis involves complex interactions between the immune and coagulation systems.
  • The link between coagulation and immunity in atherogenesis, particularly via interleukin-1 alpha (IL-1α) activation by thrombin, is not fully understood.

Purpose of the Study:

  • To investigate the role of thrombin-mediated IL-1α activation in atherosclerosis development.
  • To characterize the impact of inhibiting this pathway on atherosclerotic plaque formation and stability.

Main Methods:

  • Generated a novel knock-in mouse model (IL-1α thrombin mutant, IL-1αTM) unable to activate IL-1α via thrombin.
  • Utilized Apoe-/- mice to study atherosclerotic plaque formation and composition.
  • Employed bone marrow chimera experiments to determine the cellular origin of thrombin-activated IL-1α.

Main Results:

  • IL-1αTM/Apoe-/- mice exhibited reduced atherosclerotic plaque formation and T-cell infiltration compared to controls.
  • However, plaques in IL-1αTM/Apoe-/- mice showed decreased vascular smooth muscle cells, collagen, and fibrous caps, indicating increased instability.
  • Thrombin inhibitors' anti-atherogenic effects were diminished in IL-1αTM/Apoe-/- mice, suggesting mediation through IL-1α.
  • Thrombin-activated IL-1α originates from both vessel wall and myeloid cells.

Conclusions:

  • The atherogenic effects of coagulation are partly mediated by thrombin cleavage of IL-1α.
  • This highlights the crucial interplay between coagulation and immunity in atherosclerosis.
  • Targeting IL-1α and/or thrombin presents potential therapeutic strategies.
  • IL-1α may also influence atherosclerotic plaque stabilization.
Abstract

Keywords:
AtherosclerosisCoagulationIL-1InflammationThrombin

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