| Summary: | <p>Macrophages are integral to the pathogenesis of atherosclerosis, but the contribution of distinct macrophage subsets to disease remains poorly defined. Using single cell technologies and conditional ablation via a <em>LysM</em><sup>Cre+</sup> <em>Clec4a2</em><sup>flox/DTR</sup> mouse strain, we demonstrate that the expression of the C-type lectin receptor CLEC4A2 is a distinguishing feature of vascular resident macrophages endowed with athero-protective properties. Through genetic deletion and competitive bone marrow chimera experiments, we identify CLEC4A2 as an intrinsic regulator of macrophage tissue adaptation by promoting a bias in monocyte-to-macrophage in situ differentiation towards colony stimulating factor 1 (CSF1) in vascular health and disease. During atherogenesis, CLEC4A2 deficiency results in loss of resident vascular macrophages and their homeostatic properties causing dysfunctional cholesterol metabolism and enhanced toll-like receptor triggering, exacerbating disease. Our study demonstrates that CLEC4A2 licenses monocytes to join the vascular resident macrophage pool, and that CLEC4A2-mediated macrophage homeostasis is critical to combat cardiovascular disease.</p>
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