Thrombin activated Interleukin-1α drives atherogenesis, but also promotes VSMC proliferation and collagen production.

Atherosclerosis is driven by multiple processes across multiple body systems. For example, the innate immune system drives both atherogenesis and plaque rupture via inflammation, while coronary artery-occluding thrombi formed by the coagulation system cause myocardial infarction and death. However, the interplay between these systems during atherogenesis is understudied. We recently showed that coagulation and immunity are fundamentally linked by the activation of Interleukin-1α (IL-1α) by thrombin, and generated a novel knock-in mouse in which thrombin cannot activate endogenous IL-1α (IL-1αTM). Here, we show significantly reduced atherosclerotic plaque formation in IL-1αTM/Apoe-/- mice compared to Apoe-/- and reduced T cell infiltration. However, IL-1αTM/Apoe-/- plaques have reduced vascular smooth muscle cells (VSMCs), collagen and fibrous caps, indicative of a more unstable phenotype. Interestingly, the reduced atherogenesis seen with thrombin inhibition was absent in IL-1αTM/Apoe-/- mice, suggesting that thrombin inhibitors can affect atherosclerosis via reduced IL-1α activation. Finally, bone marrow chimeras show that thrombin activated IL-1α is derived from both vessel wall and myeloid cells. Together, we reveal that the atherogenic effect of ongoing coagulation is, in part, mediated via thrombin cleavage of IL-1α. This highlights the importance of interplay between systems during disease and the potential for therapeutically targeting IL-1α and/or thrombin, but also forewarns that IL-1 may have a role in plaque stabilisation. © The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.

Citation

Burzynski C Laura, Maria A Morales-Maldonado, Amanda Rodgers, Lauren A Kitt, Melanie Humphry, Nichola Figg, Martin R Bennett, Murray C H Clarke. Thrombin activated Interleukin-1α drives atherogenesis, but also promotes VSMC proliferation and collagen production. Cardiovascular research. 2023 Jun 13

PMID: 37309666

search → result