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The Dendritic Cell Receptor DNGR-1 Promotes the Development of Atherosclerosis in Mice.

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Haddad, Yacine 
Lahoute, Charlotte 
Clément, Marc 
Laurans, Ludivine 
Metghalchi, Sarvenaz 


RATIONALE: Necrotic core formation during the development of atherosclerosis is associated with a chronic inflammatory response and promotes accelerated plaque development and instability. However, the molecular links between necrosis and the development of atherosclerosis are not completely understood. Clec9a (C-type lectin receptor) or DNGR-1 (dendritic cell NK lectin group receptor-1) is preferentially expressed by the CD8α+ subset of dendritic cells (CD8α+ DCs) and is involved in sensing necrotic cells. We hypothesized that sensing of necrotic cells by DNGR-1 plays a determinant role in the inflammatory response of atherosclerosis. OBJECTIVE: We sought to address the impact of total, bone marrow-restricted, or CD8α+ DC-restricted deletion of DNGR-1 on atherosclerosis development. METHODS AND RESULTS: We show that total absence of DNGR-1 in Apoe (apolipoprotein e)-deficient mice (Apoe-/-) and bone marrow-restricted deletion of DNGR-1 in Ldlr (low-density lipoprotein receptor)-deficient mice (Ldlr-/-) significantly reduce inflammatory cell content within arterial plaques and limit atherosclerosis development in a context of moderate hypercholesterolemia. This is associated with a significant increase of the expression of interleukin-10 (IL-10). The atheroprotective effect of DNGR-1 deletion is completely abrogated in the absence of bone marrow-derived IL-10. Furthermore, a specific deletion of DNGR-1 in CD8α+ DCs significantly increases IL-10 expression, reduces macrophage and T-cell contents within the lesions, and limits the development of atherosclerosis. CONCLUSIONS: Our results unravel a new role of DNGR-1 in regulating vascular inflammation and atherosclerosis and potentially identify a new target for disease modulation.



DNGR-1, atherosclerosis, dendritic cell, inflammation, interleukin-10, necrosis, Animals, Atherosclerosis, Dendritic Cells, Interleukin-10, Lectins, C-Type, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, Immunologic

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Circ Res

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Ovid Technologies (Wolters Kluwer Health)
British Heart Foundation (RG/15/11/31593)