P2Y6 Receptor Potentiates Pro-Inflammatory Responses in Macrophages and Exhibits Differential Roles in Atherosclerotic Lesion Development

Background

P2Y₆, a purinergic receptor for UDP, is enriched in atherosclerotic lesions and is implicated in pro-inflammatory responses of key vascular cell types and macrophages. Evidence for its involvement in atherogenesis, however, has been lacking. Here we use cell-based studies and three murine models of atherogenesis to evaluate the impact of P2Y₆ deficiency on atherosclerosis.

Methodology/Principal Findings

Cell-based studies in 1321N1 astrocytoma cells, which lack functional P2Y₆ receptors, showed that exogenous expression of P2Y₆ induces a robust, receptor- and agonist-dependent secretion of inflammatory mediators IL-8, IL-6, MCP-1 and GRO1. P2Y₆-mediated inflammatory responses were also observed, albeit to a lesser extent, in macrophages endogenously expressing P2Y₆ and in acute peritonitis models of inflammation. To evaluate the role of P2Y₆ in atherosclerotic lesion development, we used P2Y₆-deficient mice in three mouse models of atherosclerosis. A 43% reduction in aortic arch plaque was observed in high fat-fed LDLR knockout mice lacking P2Y₆ receptors in bone marrow-derived cells. In contrast, no effect on lesion development was observed in fat-fed whole body P2Y₆xLDLR double knockout mice. Interestingly, in a model of enhanced vascular inflammation using angiotensin II, P2Y₆ deficiency enhanced formation of aneurysms and exhibited a trend towards increased atherosclerosis in the aorta of LDLR knockout mice.

Conclusions

P2Y₆ receptor augments pro-inflammatory responses in macrophages and exhibits a pro-atherogenic role in hematopoietic cells. However, the overall impact of whole body P2Y₆ deficiency on atherosclerosis appears to be modest and could reflect additional roles of P2Y₆ in vascular disease pathophysiologies, such as aneurysm formation.