| Abstract |
Objective: 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.
Approach and results: 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.
Conclusions: 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.
|
| MeSH term(s) |
Angiogenesis Inhibitors/pharmacology ; Animals ; Antibodies, Monoclonal/pharmacology ; Cells, Cultured ; Digoxin/pharmacology ; Disease Models, Animal ; Ependymoglial Cells/drug effects ; Ependymoglial Cells/immunology ; Ependymoglial Cells/metabolism ; Hyperoxia/complications ; Interleukin-17/antagonists & inhibitors ; Interleukin-17/genetics ; Interleukin-17/metabolism ; Mice, Inbred C57BL ; Microglia/drug effects ; Microglia/immunology ; Microglia/metabolism ; Microglia/pathology ; Nuclear Receptor Subfamily 1, Group F, Member 3/antagonists & inhibitors ; Nuclear Receptor Subfamily 1, Group F, Member 3/genetics ; Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism ; Placenta Growth Factor/metabolism ; Rats, Sprague-Dawley ; Retina/drug effects ; Retina/immunology ; Retina/metabolism ; Retina/pathology ; Retinal Ganglion Cells/drug effects ; Retinal Ganglion Cells/immunology ; Retinal Ganglion Cells/metabolism ; Retinal Neovascularization/immunology ; Retinal Neovascularization/metabolism ; Retinal Neovascularization/pathology ; Retinal Neovascularization/prevention & control ; Retinopathy of Prematurity/immunology ; Retinopathy of Prematurity/metabolism ; Retinopathy of Prematurity/pathology ; Retinopathy of Prematurity/prevention & control ; Signal Transduction/drug effects ; Sulfonamides/pharmacology ; Thiazoles/pharmacology ; Tumor Necrosis Factor-alpha/metabolism ; Vascular Endothelial Growth Factor A/metabolism |
| Chemical Substances |
Angiogenesis Inhibitors ; Antibodies, Monoclonal ; Il17a protein, mouse ; Il17a protein, rat ; Interleukin-17 ; Nuclear Receptor Subfamily 1, Group F, Member 3 ; Pgf protein, mouse ; Pgf protein, rat ; Rorc protein, mouse ; Rorc protein, rat ; SR1001 ; Sulfonamides ; Thiazoles ; Tumor Necrosis Factor-alpha ; Vascular Endothelial Growth Factor A ; vascular endothelial growth factor A, mouse ; vascular endothelial growth factor A, rat ; Placenta Growth Factor (144589-93-5) ; Digoxin (73K4184T59) |
| Language |
English |
| Publishing date |
2016-04-07 |
| Publishing country |
United States |
| Document type |
Journal Article |
| ZDB-ID |
1221433-4 |
| ISSN |
1524-4636 ; 1079-5642 |
| ISSN (online) |
1524-4636 |
| ISSN |
1079-5642 |
| DOI |
10.1161/ATVBAHA.115.307080 |
| Database |
MEDical Literature Analysis and Retrieval System OnLINE |
