Genetic inhibition of CARD9 accelerates the development of atherosclerosis in mice through CD36 dependent-defective autophagy
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Published:2023-08-01
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Zhang YujiaoORCID, Vandestienne MarieORCID, Lavillegrand Jean-Rémi, Joffre Jeremie, Santos-Zas Icia, Lavelle Aonghus, Zhong Xiaodan, Le Goff WilfriedORCID, Guérin Maryse, Al-Rifai RidaORCID, Laurans Ludivine, Bruneval Patrick, Guérin CoralieORCID, Diedisheim MarcORCID, Migaud MelanieORCID, Puel Anne, Lanternier Fanny, Casanova Jean-Laurent, Cochain Clément, Zernecke Alma, Saliba Antoine-EmmanuelORCID, Mokry MichalORCID, Silvestre Jean-SebastienORCID, Tedgui AlainORCID, Mallat Ziad, Taleb SorayaORCID, Lenoir OliviaORCID, Vindis Cécile, Camus Stéphane M.ORCID, Sokol HarryORCID, Ait-Oufella HafidORCID
Abstract
AbstractCaspase recruitment-domain containing protein 9 (CARD9) is a key signaling pathway in macrophages but its role in atherosclerosis is still poorly understood. Global deletion of Card9 in Apoe-/- mice as well as hematopoietic deletion in Ldlr-/- mice increases atherosclerosis. The acceleration of atherosclerosis is also observed in Apoe-/-Rag2-/-Card9-/- mice, ruling out a role for the adaptive immune system in the vascular phenotype of Card9 deficient mice. Card9 deficiency alters macrophage phenotype through CD36 overexpression with increased IL-1β production, increased lipid uptake, higher cell death susceptibility and defective autophagy. Rapamycin or metformin, two autophagy inducers, abolish intracellular lipid overload, restore macrophage survival and autophagy flux in vitro and finally abolish the pro-atherogenic effects of Card9 deficiency in vivo. Transcriptomic analysis of human CARD9-deficient monocytes confirms the pathogenic signature identified in murine models. In summary, CARD9 is a key protective pathway in atherosclerosis, modulating macrophage CD36-dependent inflammatory responses, lipid uptake and autophagy.
Funder
Fondation de l'Avenir pour la Recherche Médicale Appliquée
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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