Myeloid But Not Endothelial Expression of the CB2 Receptor Promotes Atherogenesis in the Context of Elevated Levels of the Endocannabinoid 2-Arachidonoylglycerol

Abstract

The endocannabinoid 2-arachidonoylglycerol (2-AG) is an inflammatory mediator and ligand for the cannabinoid receptors CB1 and CB2. We investigated the atherogenic mechanisms set in motion by 2-AG. Therefore, we created two atherosclerotic mouse models with distinct cell-specific knockouts of the CB2 receptor on either myeloid or endothelial cells. These mice were treated with JZL184, resulting in elevated plasma levels of 2-AG. After a high-fat high-cholesterol diet, atherosclerotic plaques were analyzed. The atherogenic effect of 2-AG was abrogated in mice lacking myeloid expression of the CB2 receptor but not in mice lacking endothelial expression of the CB2 receptor. In vitro, treatment of human monocytes with 2-AG led to the increased production of reactive oxygen species (ROS) and IL-1β. In conclusion, 2-AG shows an atherogenic effect in vivo, dependent on the presence of the CB2 receptor on myeloid cells. In addition, our in vitro data revealed 2-AG to promote inflammatory signalling in monocytes. Graphical abstract: 2-Arachidonoylglycerol shows an atherogenic effect that is abrogated in mice lacking myeloid expression of the CB2 receptor. [Figure not available: see fulltext.]