Genetic inhibition of CARD9 accelerates the development of atherosclerosis in mice through CD36 dependent-defective autophagy
Zhang, Yujiao; Vandestienne, Marie; Lavillegrand, Jean Rémi; Joffre, Jeremie; Santos-Zas, Icia; Lavelle, Aonghus; Zhong, Xiaodan; Le Goff, Wilfried; Guérin, Maryse; Al-Rifai, Rida; Laurans, Ludivine; Bruneval, Patrick; Guérin, Coralie; Diedisheim, Marc; Migaud, Melanie; Puel, Anne; Lanternier, Fanny; Casanova, Jean Laurent; Cochain, Clément; Zernecke, Alma; Saliba, Antoine Emmanuel; Mokry, Michal; Silvestre, Jean Sebastien; Tedgui, Alain; Mallat, Ziad; Taleb, Soraya; Lenoir, Olivia; Vindis, Cécile; Camus, Stéphane M.; Sokol, Harry; Ait-Oufella, Hafid
(2023) Nature Communications, volume 14, issue 1
(Article)
Abstract
Caspase 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
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-/- 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.
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Keywords: General Chemistry, General Biochemistry,Genetics and Molecular Biology, General Physics and Astronomy
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Funding Information: This work was supported by Inserm (H.A.O. and Z.M.), Nouvelle Société Française d’Athérosclérose (Y.Z.), the Fondation pour la Recherche Médicale (H.A.O. and S.T.), la Fondation Lefoulon-Delalande (Y.S.Z.), la Fondation de l’avenir, The European Research Council (Z.M.), and the British Heart Foundation (Z.M.). C. Cochain was supported by the Interdisciplinary Center for Clinical Research (IZKF, Interdisziplinäres Zentrum für Klinische Forschung), University Hospital Würzburg (Project IZKF-E-353). C.C., A.E.S., and A.Z. are supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Project-ID 453989101-SFB1525. S.C.M. received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement No 846519 and by the Fondation Lefoulon-Delalande, Paris, France. High-throughput sequencing was performed by the ICGex NGS platform of the Institut Curie supported by the grants ANR-10-EQPX-03 (Equipex) and ANR-10-INBS-09-08 (France Génomique Consortium) from the Agence Nationale de la Recherche (“Investissements d’Avenir” program), by the ITMO-Cancer Aviesan (Plan Cancer III) and by the SiRIC-Curie program (SiRIC Grant INCa-DGOS-465 and INCa-DGOS-Inserm_12554). Data management, quality control, and primary analysis were performed by the Bioinformatics platform of the Institut Curie.” A.P. and M.M. were supported by the French National Research Agency (ANR) under the “Investments for the future” program (ANR-10-IAHU-01), the ANR-FNS LTh-MSMD-CMCD (ANR-18-CE93-0008-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), and the National Institute of Allergy and Infectious Diseases of the NIH (grant no. R01AI127564). Publisher Copyright: © 2023, The Author(s).
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