TY - JOUR
T1 - Genetic inhibition of CARD9 accelerates the development of atherosclerosis in mice through CD36 dependent-defective autophagy
AU - Zhang, Yujiao
AU - Vandestienne, Marie
AU - Lavillegrand, Jean Rémi
AU - Joffre, Jeremie
AU - Santos-Zas, Icia
AU - Lavelle, Aonghus
AU - Zhong, Xiaodan
AU - Le Goff, Wilfried
AU - Guérin, Maryse
AU - Al-Rifai, Rida
AU - Laurans, Ludivine
AU - Bruneval, Patrick
AU - Guérin, Coralie
AU - Diedisheim, Marc
AU - Migaud, Melanie
AU - Puel, Anne
AU - Lanternier, Fanny
AU - Casanova, Jean Laurent
AU - Cochain, Clément
AU - Zernecke, Alma
AU - Saliba, Antoine Emmanuel
AU - Mokry, Michal
AU - Silvestre, Jean Sebastien
AU - Tedgui, Alain
AU - Mallat, Ziad
AU - Taleb, Soraya
AU - Lenoir, Olivia
AU - Vindis, Cécile
AU - Camus, Stéphane M.
AU - Sokol, Harry
AU - Ait-Oufella, Hafid
N1 - 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).
PY - 2023/8
Y1 - 2023/8
N2 - 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 -/- 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.
AB - 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 -/- 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.
UR - http://www.scopus.com/inward/record.url?scp=85166063474&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-40216-x
DO - 10.1038/s41467-023-40216-x
M3 - Article
C2 - 37528097
AN - SCOPUS:85166063474
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4622
ER -