GPR109A as an Anti-Inflammatory Receptor in Retinal Pigment Epithelial Cells and Its Relevance to Diabetic Retinopathy

PURPOSE. Retinal pigment epithelium (RPE) expresses GPR109A, a receptor for the vitamin niacin and the ketone body beta-hydroxybutyrate (beta-HB). Because diabetes results in elevated levels of beta-HB, here we studied expression of the receptor in diabetic retina. We also investigated its functional relevance in RPE. METHODS. Retinal expression of GPR109A in diabetic mice and postmortem human eyes was evaluated by quantitative PCR (qPCR). ARPE-19 cells and primary wild-type and Gpr109a(-/-) mouse RPE cells were exposed to TNF-alpha in the presence or absence of niacin or beta-HB, followed by analysis of IL-6 and Ccl2 expression via real-time qPCR and ELISA. RESULTS. GPR109A expression was increased in diabetic mouse and human retina. TNF-alpha increased the expression and secretion of IL-6 and Ccl2 in ARPE-19 cells. Niacin and beta-HB suppressed these effects, implicating GPR109A as the target responsible for mediation of the observed effects. Primary RPE cells from wild-type mice behaved similarly. In contrast, GPR109A ligands failed to suppress TNF-alpha-induced expression and secretion of IL-6 and Ccl2 in primary RPE cells from Gpr109a(-/-) mice, confirming that the observed anti-inflammatory effects were mediated specifically by Gpr109a. CONCLUSIONS. GPR109A plays an anti-inflammatory role in RPE and its expression is upregulated in diabetes. Inflammation is a key causative factor in the pathogenesis of diabetic retinopathy. We speculate that the increased expression of GPR109A and elevation of its ligand beta-HB in diabetes are mechanisms by which the tissue attempts to fight inflammation in this disease. Pharmacological activation of GPR109A may therefore have therapeutic potential in clinical management of diabetic retinopathy. (Invest Ophthalmol Vis Sci. 2012; 53: 2208-2217) DOI:10.1167/iovs.11-8447