title: Inhibition of the Nuclear Receptor RORγ and Interleukin-17A Suppresses Neovascular Retinopathy: Involvement of Immunocompetent Microglia.
abstract: Although inhibitors of vascular endothelial growth factor (VEGF) provide benefit for the management of neovascular retinopathies, their use is limited to end-stage disease and some eyes are resistant. We hypothesized that retinoic acid-related orphan nuclear receptor γ (RORγ) and its downstream effector, interleukin (IL)-17A, upregulate VEGF and hence are important treatment targets for neovascular retinopathies.
  
  
  
  Utilizing a model of oxygen-induced retinopathy, confocal microscopy and flow cytometry, we identified that retinal immunocompetent cells, microglia, express IL-17A. This was confirmed in primary cultures of rat retinal microglia, where hypoxia increased IL-17A protein as well as IL-17A, RORγ, and tumor necrosis factor-α mRNA, which were reduced by the RORγ inhibitor, digoxin, and the RORα/RORγ inverse agonist, SR1001. By contrast, retinal macroglial Müller cells and ganglion cells, key sources of VEGF in oxygen-induced retinopathy, did not produce IL-17A when exposed to hypoxia and IL-1β. However, they expressed IL-17 receptors, and in response to IL-17A, secreted VEGF. This suggested that RORγ and IL-17A inhibition might attenuate neovascular retinopathy. Indeed, digoxin and SR1001 reduced retinal vaso-obliteration, neovascularization, and vascular leakage as well as VEGF and VEGF-related placental growth factor. Digoxin and SR1001 reduced microglial-derived IL-17A and Müller cell and ganglion cell damage. The importance of IL-17A in oxygen-induced retinopathy was confirmed by IL-17A neutralization reducing vasculopathy, VEGF, placental growth factor, tumor necrosis factor-α, microglial density and Müller cell, and ganglion cell injury.
  
  
  
  Our findings indicate that an RORγ/IL-17A axis influences VEGF production and neovascular retinopathy by mechanisms involving neuroglia. Inhibition of RORγ and IL-17A may have potential for the improved treatment of neovascular retinopathies.
authors.affiliation: From the Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Dean M
authors.initials: DM
authors.lastname: Talia
authors.affiliation: From the Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Devy
authors.initials: D
authors.lastname: Deliyanti
authors.affiliation: From the Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Alex
authors.initials: A
authors.lastname: Agrotis
authors.affiliation: From the Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia. jennifer.wilkinson-berka@monash.edu.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Wilkinson-Berka
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002478:Cells, Cultured; D004077:Digoxin / Q000494:pharmacology*; D004195:Disease Models, Animal; D063928:Ependymoglial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018496:Hyperoxia / Q000150:complications; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000072483:Placenta Growth Factor / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015861:Retinal Neovascularization / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012178:Retinopathy of Prematurity / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; C098680:Il17a protein, mouse; C515934:Il17a protein, rat; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C000608037:Pgf protein, mouse; C000608038:Pgf protein, rat; C539901:Rorc protein, mouse; C539902:Rorc protein, rat; C558809:SR1001; D013449:Sulfonamides; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C467498:vascular endothelial growth factor A, rat; D000072483:Placenta Growth Factor; D004077:Digoxin
keywords: ganglion cells; interleukin-17; microglia; retina; retinoic acid receptor