C-type lectin receptor CLEC4A2 promotes tissue adaptation of macrophages and protects against atherosclerosis

Inhye Park, Michael E. Goddard, Jennifer E. Cole, Natacha Zanin, Leo-Pekka Lyytikäinen, Terho Lehtimäki, Evangelos Andreakos, Marc Feldmann, Irina Udalova, Ignat Drozdov and Claudia Monaco ()
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Inhye Park: University of Oxford
Michael E. Goddard: University of Oxford
Jennifer E. Cole: University of Oxford
Natacha Zanin: University of Oxford
Leo-Pekka Lyytikäinen: Tampere University
Terho Lehtimäki: Tampere University
Evangelos Andreakos: Center for Clinical, Experimental Surgery and Translational Research
Marc Feldmann: University of Oxford
Irina Udalova: University of Oxford
Ignat Drozdov: Bering Limited
Claudia Monaco: University of Oxford

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-021-27862-9

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