C-type Lectin Receptor Clec9a on Cd8a+Dendritic Cells Promotes the Development of Atherosclerosis in Mice

Necrotic core formation during the development of atherosclerosis is associated with a chronic inflammatory response and promotes accelerated plaque development and instability. We hypothesized that sensing of necrotic cells by CLEC9A, a C-type lectin receptors selectively expressed by the CD8α + subset of dendritic cells (CD8α + DCs), plays a determinant role in the inflammatory response of atherosclerosis. Reconstitution of lethally-irradiated Ldlr-/- with bone marrow from CLEC9A-/- mice significantly reduced atherosclerotic lesion size in aortic root after 5 weeks of high fat diet (HFD) (-45%, p=0,0059) and after 7 weeks of HFD (-40%, p=0,0017), as compared to mice transplanted with wild-type bone marrow-derived cells. However, no effect of CLEC9A was observed after 13 weeks of HFD (p=0,4996), suggesting early effect of CLEC9A on atherosclerosis development. The same phenotype was observed in 20-week-old Apoe-/-CLEC9A-/- compared to Apoe-/- mice put on chow diet (-50%, p=0,0022). Interestingly, an increase of IL-10 expression (+60%, p=0,0093) was observed in spleens of mice deficient for CLEC9A. Furthermore, the beneficial effect observed in CLEC9A-/- was abolished in CLEC9A-/-IL-10-/- compared to IL-10-/- (p=0,4452). Moreover, a specific deletion of Clec9a in CD8α + DC cells significantly increases Il10 expression, reduces macrophage and T cell contents within the lesions, and significantly limits the development of atherosclerosis. In conclusion, our results identify a new role of Clec9a in regulating vascular inflammation and atherosclerosis development and potentially identify a new target for disease modulation.