Genetic inhibition of CARD9 accelerates the development of atherosclerosis in mice through CD36 dependent-defective autophagy

Yujiao Zhang, Marie Vandestienne, Jean-Rémi Lavillegrand, Jeremie Joffre, Icia Santos-Zas, Aonghus Lavelle, Xiaodan Zhong, Wilfried Le Goff, Maryse Guérin, Rida Al-Rifai, Ludivine Laurans, Patrick Bruneval, Coralie Guérin, Marc Diedisheim, Melanie Migaud, Anne Puel, Fanny Lanternier, Jean-Laurent Casanova, Clément Cochain, Alma Zernecke, Antoine-Emmanuel Saliba, Michal Mokry, Jean-Sebastien Silvestre, Alain Tedgui, Ziad Mallat, Soraya Taleb, Olivia Lenoir, Cécile Vindis, Stéphane M. Camus, Harry Sokol and Hafid Ait-Oufella ()
Additional contact information
Yujiao Zhang: Université Paris Cité
Marie Vandestienne: Université Paris Cité
Jean-Rémi Lavillegrand: Université Paris Cité
Jeremie Joffre: Université Paris Cité
Icia Santos-Zas: Université Paris Cité
Aonghus Lavelle: Sorbonne Université
Xiaodan Zhong: Université Paris Cité
Wilfried Le Goff: Inserm UMRS1166, ICAN, Institute of CardioMetabolism and Nutrition, Hôpital Pitié-Salpêtrière (AP-HP)
Maryse Guérin: Inserm UMRS1166, ICAN, Institute of CardioMetabolism and Nutrition, Hôpital Pitié-Salpêtrière (AP-HP)
Rida Al-Rifai: Université Paris Cité
Ludivine Laurans: Université Paris Cité
Patrick Bruneval: Université Paris Cité
Coralie Guérin: Institut Curie, Cytometry Platform
Marc Diedisheim: Clinique Saint Gatien Alliance (NCT+), 37540 Saint-Cyr-sur-Loire, France; Institut Necker-Enfants Malades (INEM), Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253
Melanie Migaud: Necker Branch, INSERM U1163, Imagine Institute
Anne Puel: Necker Branch, INSERM U1163, Imagine Institute
Fanny Lanternier: Necker Branch, INSERM U1163, Imagine Institute
Jean-Laurent Casanova: Necker Branch, INSERM U1163, Imagine Institute
Clément Cochain: University Hospital Wuerzburg
Alma Zernecke: University Hospital Wuerzburg
Antoine-Emmanuel Saliba: Helmholtz-Center for Infection Research (HZI)
Michal Mokry: University Medical Center Utrecht, University Utrecht
Jean-Sebastien Silvestre: Université Paris Cité
Alain Tedgui: Université Paris Cité
Ziad Mallat: Université Paris Cité
Soraya Taleb: Université Paris Cité
Olivia Lenoir: Université Paris Cité
Cécile Vindis: CIC 1436/CARDIOMET, Inserm
Stéphane M. Camus: Université Paris Cité
Harry Sokol: Sorbonne Université
Hafid Ait-Oufella: Université Paris Cité

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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-/-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.

Date: 2023
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DOI: 10.1038/s41467-023-40216-x

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