Abstract
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 LysMCre+Clec4a2flox/DTR 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.
Highlights
Macrophages are integral to the pathogenesis of atherosclerosis, but the contribution of distinct macrophage subsets to disease remains poorly defined
Atherogenesis promoted a reduction in the representation of this aortic macrophage population to 73.7 ± 2.0% in high fat diet (HFD)-fed apolipoprotein E-deficient (ApoE)−/− mice
CD11c+CD44+ macrophages significantly increased with atherosclerosis from 3.8 ± 0.4% in wild type (WT) to 26.3 ± 2.1% in ApoE−/− (HFD) mice
Summary
Macrophages are integral to the pathogenesis of atherosclerosis, but the contribution of distinct macrophage subsets to disease remains poorly defined. The majority of lymphatic-vessel endothelial hyaluronan receptor-1 (Lyve1)+ adventitial macrophages are replenished by bone marrow (BM)derived monocytes after birth[8], while arterial intimal resident macrophages are replaced by monocytes during early atherosclerosis[6]. The former regulate collagen production in smooth-muscle cells and prevent unfavourable arterial remodelling[7] while the latter are responsible for cholesterol uptake and initiation of vascular inflammation by producing interleukin-1β (IL-1β)[6]. CLEC4A2 promotes appropriate tissue adaptation of vascular macrophages ensuring homeostasis of the vessel wall and combating atherosclerosis
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