title: GPR109A as an anti-inflammatory receptor in retinal pigment epithelial cells and its relevance to diabetic retinopathy.
abstract: OBJECTIVE
  Retinal pigment epithelium (RPE) expresses GPR109A, a receptor for the vitamin niacin and the ketone body β-hydroxybutyrate (β-HB). Because diabetes results in elevated levels of β-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-α in the presence or absence of niacin or β-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-α increased the expression and secretion of IL-6 and Ccl2 in ARPE-19 cells. Niacin and β-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-α-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 β-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.
authors.affiliation: Department of Biochemistry and Molecular Biology, and the Vision Science Discovery Institute, Georgia Health Sciences University, Augusta, Georgia 30912, USA.
authors.forename: Deeksha
authors.initials: D
authors.lastname: Gambhir
authors.forename: Sudha
authors.initials: S
authors.lastname: Ananth
authors.forename: Rajalakshmi
authors.initials: R
authors.lastname: Veeranan-Karmegam
authors.forename: Selvakumar
authors.initials: S
authors.lastname: Elangovan
authors.forename: Shanterian
authors.initials: S
authors.lastname: Hester
authors.forename: Eric
authors.initials: E
authors.lastname: Jennings
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.forename: Julian J
authors.initials: JJ
authors.lastname: Nussbaum
authors.forename: Sylvia B
authors.initials: SB
authors.lastname: Smith
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Thangaraju
authors.forename: Vadivel
authors.initials: V
authors.lastname: Ganapathy
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Martin
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000494:pharmacology; D000368:Aged; D000818:Animals; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000235:genetics* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009525:Niacin / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D011978:Receptors, Nicotinic / Q000235:genetics*; D012160:Retina / Q000187:drug effects / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C111835:CCL2 protein, human; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C530636:HCAR2 protein, human; C473652:Hcar2 protein, mouse; C508600:IL6 protein, human; D015850:Interleukin-6; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D014409:Tumor Necrosis Factor-alpha; D009525:Niacin; D020155:3-Hydroxybutyric Acid