The Dendritic Cell Receptor DNGR-1 Promotes the Development of Atherosclerosis in MiceNovelty and Significance
This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.
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.
- Received March 10, 2017.
- Revision received June 6, 2017.
- Accepted June 9, 2017.
- © 2017 American Heart Association, Inc.