|Clin Res Cardiol (2021). 10.1007/s00392-021-01933-9
|An inflammasome-independent role for NLRP3 in mediating atheromatous plaque macrophage proliferation|
|F. Remmersmann1, C. Härdtner1, B. Dufner1, T.-S. Dederichs1, C. Bode1, I. Hilgendorf1|
|1Klinik für Kardiologie und Angiologie I, Universitäts-Herzzentrum Freiburg - Bad Krozingen GmbH, Freiburg im Breisgau;|
Background: Macrophage accumulation links to plaque progression in atherosclerosis and limiting macrophage accumulation halts or even reverses plaque progression. We previously showed that local proliferation dominates macrophage proliferation during plaque progression, and systemic cholesterol lowering suppresses macrophage proliferation resulting in plaque regression. The intracellular pathways regulating macrophage proliferation have remained ill-defined.
Objectives: We aim at identifying mediators of atheromatous plaque macrophage proliferation using mixed bone marrow chimeric mouse models, in vivo, and human plaque tissue cell cultures, in vitro.
Methods and Results: Macrophages deficient in scavenger receptors CD36 and Msr1, which mediate cholesterol-rich lipoprotein uptake, proliferated less compared to wild-type macrophages in the same plaque exposed to the same lipid levels in our murine models. Deficiency of NLRP3, but not the other inflammasome components ASC and Caspase 1, limited macrophage proliferation. In line, IL-1 receptor deficiency did not impact macrophage proliferation, indicative of an NLRP3-dependent, but inflammasome-independent effect. Inhibition of NLRP3 by MCC950 in human carotid artery tissue cultures resulted in the suppression of intra-plaque macrophage proliferation and IL-1beta release. Supplementation with IL-1beta, however, did not restore macrophage proliferation in line with our murine data.
Conclusion: We identified a novel role for NLRP3, independent of the canonical inflammasome pathway, in driving macrophage proliferation in atherosclerotic plaques representing a druggable target with relevance for humans.