O041 Predominant role of macrophage-derived IL-1alpha but not IL-1beta in atherosclerosis

Abstract

Introduction Atherosclerosis is a chronic inflammatory condition affecting the arterial vasculature. Its clinical manifestations, such as myocardial infarction and ischemic stroke, are the leading causes of morbidity and mortality worldwide. IL-1 receptor (IL-1R)-signaling severely exacerbates the chronic vascular inflammation that drives disease progression. While the contribution of inflammasome-activation to atherogenesis in vivo remains controversial, IL-1beta is currently targeted in clinical trials. However, as both IL-1alpha and IL-1beta signal via IL-1R and exhibit overlapping functions, the relative contribution of each IL-1 isoform to atherogenesis is still unclear. Methods We have compared the impact of both IL-1 isoforms on disease progression in mouse models of atherosclerosis, and have investigated the mechanisms of IL-1alpha versus IL-1beta induction by different atherogenic lipids in macrophage-foam cells. Results Here we report that deficiency in hematopoietic IL-1alpha markedly reduced atherosclerosis by 51%, whereas no significant effect was observed in mice lacking BM-derived IL-1beta, suggesting that macrophage-derived IL-1alpha - and not IL-1beta - represents the pro-atherogenic IL-1 isoform. Moreover, our study identified the fatty acid oleic acid, which is abundant amongst plaque lipids, as a selective trigger of potent IL-1alpha - but not IL-1beta - responses in foam cells. This atherogenic IL-1alpha production was independent of inflammasome activation, but surprisingly required the cellular expression of pro-IL-1beta. Hence, IL-1beta−/− macrophages were unable to secrete IL-1alpha, which may explain the conflicting reports showing reduced atherosclerosis in IL-1beta-deficient mice. Furthermore, feeding of an oleate-enriched but cholesterol-free diet aggravated atherogenesis, suggesting that IL-1alpha is both necessary and sufficient to induce the development of atherosclerotic plaques. Conclusion Taken together, our data demonstrate that macrophage-foam cells promote atherogenesis primarily through production of IL-1alpha, and therefore suggest that the role of inflammasome activation and IL-1beta in atherosclerosis may need to be reconsidered. Most importantly, they indicate that IL-1alpha and not IL-1beta should be targeted therapeutically in patients with cardiovascular disease.