Autor: |
Yujiao ZHANG, Marie Vandestienne, Jean-Rémi Lavillegrand, Jeremie Joffre, Icia Santos-Zas, Aonghus Lavelle, Xiadan Zhong, Wilfried Le Goff, Maryse Guerin, Olivia Lenoir, Ludivine Laurans, Patrick Bruneval, Coralie Guérin, Marc Diedisheim, Melanie Migaud, Anne Puel, Fanny Lanternier, Jean-Laurent Casanova, Clement Cochain, Alma Zernecke, Antoine-Emmanuel Saliba, Jean-sébastien Silvestre, Alain Tedgui, Ziad Mallat, Soraya Taleb, Cecile Vindis, Stephane Camus, Harry Sokol, Hafid Ait-Oufella |
Rok vydání: |
2022 |
Popis: |
Macrophage-mediated innate immune responses contribute to the initiation, progression and complications of atherosclerosis. However, the underlying pathways linking activation of macrophages to atherosclerotic plaque develoment are still poorly understood. We hypothesized that activation of caspase recruitment-domain containing protein 9 (CARD9) plays a determinant role in pro-atherogenic responses in macrophages. We showed that global deletion of Card9 in male Apoe−/− mice as well as hematopoietic deletion of Card9 in female Ldlr−/− mice increased atherosclerosis. Card9−/− chimeric animals displayed more inflammatory atherosclerotic plaques and decreased systemic Th17 responses when compared to Card9+/+ chimeric mice. The acceleration of atherosclerosis was also observed in Apoe−/−Rag2−/−Card9−/− mice lacking T, B, and NKT cells, ruling out a role for the adaptive immune system in the pro-atherogenic effect of Card9 deficiency. Card9 deficiency altered macrophage phenotype with increased production of pro-inflammatory cytokines, improved lipid uptake, higher cell death susceptibility and defective autophagy. Rapamycin or metformin, two autophagy inducers, abolished intracellular lipid overload, restored macrophage survival and autophagy flux in vitro and finally abolished the pro-atherogenic effects of Card9 deficiency in vivo. Card9 deficiency up-regulated Cd36 expression in macrophages, which blocked AMPK phosphorylation, a key inducer of autophagy. In the absence of Cd36, the pro-atherogenic effects of Card9 deficiency were blunted both in vitro and in vivo. Transcriptomic analysis of human monocytes isolated from CARD9-deficient patients confirmed the pathogenic signature identified in murine models. In summary, we identified CARD9 signaling as a key protective pathway in atherosclerosis, modulating macrophage CD36-dependent inflammatory responses, lipid uptake and autophagy. |
Databáze: |
OpenAIRE |
Externí odkaz: |
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