The Dendritic Cell Receptor DNGR-1 Promotes the Development of Atherosclerosis in Mice
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. C-type lectin receptor (Clec9a) or DNGR1 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 DNGR1 plays a determinant role in the inflammatory response of atherosclerosis.
Objective: We sought to address the impact of either total, bone marrow (BM) or CD8α+ DC-restricted deletion of DNGR1 on atherosclerosis development.
Methods and Results: We show that total absence of DNGR1 in apolipoprotein e-deficient mice (Apoe-/-) mice as well as BM-restricted deletion of DNGR1 in low-density lipoprotein receptor-deficient (Ldlr-/-) mice significantly reduce inflammatory cell content within arterial plaques and limit atheroslerosis development in a context of moderate hypercholesterolemia. This is associated with a significant increase of the expression of interleukin 10 (IL10). The atheroprotective effect of DNGR1 deletion is completely abrogated in the absence of BM-derived IL10. Furthermore, a specific deletion of DNGR1 in CD8α+ DCs significantly increases IL10 expression, reduces macrophage and T cell contents within the lesions, and limits the development of atherosclerosis.
Conclusions: Our results unravel a new role of DNGR1 in regulating vascular inflammation and atherosclerosis, and potentially identify a new target for disease modulation.
- Received March 10, 2017.
- Revision received June 6, 2017.
- Accepted June 9, 2017.