Behind enemy lines: CLEC4A2 as a new ally in the fight against cardiovascular disease, hidden within the vessel wall itself

A new study challenges the widely held belief that macrophages are solely detrimental in cardiovascular disease with the discovery of a protective subset of vascular macrophages expressing the C-type lectin receptor CLEC4A2, a molecule which fosters homeostatic functions within the vessel wall.

The study identifies that CLEC4A2 discriminates homeostatic macrophages from activated states in murine atherosclerotic aortas using single cell technologies. CLEC4A2 instructs macrophages to gain their identity of resident vascular macrophages and their protective functions during atherosclerosis. Ablation of CLEC4A2⁺ resident macrophages using LysM^Cre+ Clec4a2^flox/DTR mice increases lesion development during atherogenesis. Genetic deletion of Clec4a2 results in loss of resident macrophages in the arteries, exacerbating atherosclerosis. The mechanism of the CLEC4A2 pathway was shown by using competitive in vitro and in vivo experiments that CLEC4A2 biases monocyte fate-decision from colony stimulating factor 2 (CSF2) into CSF1, which is essential for resident macrophage survival.  In addition, CLEC4A2 also maintains homeostatic properties of macrophages, by limiting immune responses to toll-like receptors and by enhancing cholesterol metabolism.

Human orthologue CLEC4A shows a strong correlation with tissue resident and M2 macrophage markers in the transcriptomic data of carotid endarterectomies. Fostering the homeostatic functions of macrophages through the CLEC4A pathway might represent a transformative therapeutic strategy for inflammatory and cardiovascular diseases.