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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Inhye Park & Michael E. Goddard & Jennifer E. Cole & Natacha Zanin & Leo-Pekka Lyytikäinen & Terho Lehtimäki & Evangelos Andreakos & Marc Feldmann & Irina Udalova & Ignat Drozdov & Claudia Monaco, 2022. "C-type lectin receptor CLEC4A2 promotes tissue adaptation of macrophages and protects against atherosclerosis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-021-27862-9
    DOI: 10.1038/s41467-021-27862-9
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    References listed on IDEAS

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    1. Charlotte L. Scott & Fang Zheng & Patrick De Baetselier & Liesbet Martens & Yvan Saeys & Sofie De Prijck & Saskia Lippens & Chloé Abels & Steve Schoonooghe & Geert Raes & Nick Devoogdt & Bart N. Lambr, 2016. "Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells," Nature Communications, Nature, vol. 7(1), pages 1-10, April.
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