Rôle de Clec9a dans l'athérosclérose

Abstract : Atherosclerosis is a chronic inflammatory disease. One of the characteristics of atherosclerotic lesions is the abnormal accumulation of apoptotic and necrotic cells, due to a deficiency of efferocytosis, which leads to the formation of the necrotic heart. The evolution of this necrotic core is also associated with an increase in inflammation and lesions of atherosclerosis, but also in the occurrence of complications such as plaque rupture. Clec9a is a C type lectin receptor, mainly expressed by a subpopulation of dendritic cells, which are the CD8α+ dendritic cells. This receptor is able to recognize a ligand expressed by necrotic cells, the actin F. The aim of our work was to find out if Clec9a, which can sense necrotic cells, could be involved in modulating the inflammation observed during the development of atherosclerosis. In this study, we have shown, in vivo with two mouse models (ApoE - / - and LDLr - / -), that the deletion of Clec9a leads to a significant decrease in the incidence of moderate hypercholesterolemia. This athero-protection observed in the absence of Clec9a, is associated with an increase in the expression of IL-10, which is an anti-atherogenic and anti-inflammatory cytokine. This athero-protective effect of the absence of Clec9a is abolished after total invalidation of IL-10. Furthermore, we report that specific knockdown of Clec9a in CD8α+-DC, in vivo, leads to a decrease in macrophage and lymphocyte infiltration in lesions, as well as an increase in IL-1 expression. 10, which promotes a decrease in lesions size. Understanding of inflammatory mechanisms in atherosclerosis is a major challenge to prevent the risk of complications such as plaque rupture or thrombosis. Thus, this work highlights a new role of Clec9a in the regulation of inflammation in atherosclerosis and could be therefore a potential therapeutic target.
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Yacine Haddad. Rôle de Clec9a dans l'athérosclérose. Biologie cellulaire. Université Sorbonne Paris Cité, 2017. Français. ⟨NNT : 2017USPCB099⟩. ⟨tel-02120724⟩

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