{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T13:04:24Z","timestamp":1790514264801,"version":"4.1.0"},"reference-count":51,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2016,6]]},"abstract":"<jats:sec>\n            <jats:title>Objective\u2014<\/jats:title>\n            <jats:p>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\u2013related orphan nuclear receptor \u03b3 (ROR\u03b3) and its downstream effector, interleukin (IL)-17A, upregulate VEGF and hence are important treatment targets for neovascular retinopathies.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results\u2014<\/jats:title>\n            <jats:p>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, ROR\u03b3, and tumor necrosis factor-\u03b1 mRNA, which were reduced by the ROR\u03b3 inhibitor, digoxin, and the ROR\u03b1\/ROR\u03b3 inverse agonist, SR1001. By contrast, retinal macroglial M\u00fcller cells and ganglion cells, key sources of VEGF in oxygen-induced retinopathy, did not produce IL-17A when exposed to hypoxia and IL-1\u03b2. However, they expressed IL-17 receptors, and in response to IL-17A, secreted VEGF. This suggested that ROR\u03b3 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 M\u00fcller 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-\u03b1, microglial density and M\u00fcller cell, and ganglion cell injury.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>Our findings indicate that an ROR\u03b3\/IL-17A axis influences VEGF production and neovascular retinopathy by mechanisms involving neuroglia. Inhibition of ROR\u03b3 and IL-17A may have potential for the improved treatment of neovascular retinopathies.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.115.307080","type":"journal-article","created":{"date-parts":[[2016,4,8]],"date-time":"2016-04-08T19:01:45Z","timestamp":1460142105000},"page":"1186-1196","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":49,"title":["Inhibition of the Nuclear Receptor ROR\u03b3 and Interleukin-17A Suppresses Neovascular Retinopathy"],"prefix":"10.1161","volume":"36","author":[{"given":"Dean M.","family":"Talia","sequence":"first","affiliation":[{"name":"From the Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devy","family":"Deliyanti","sequence":"additional","affiliation":[{"name":"From the Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Agrotis","sequence":"additional","affiliation":[{"name":"From the Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer L.","family":"Wilkinson-Berka","sequence":"additional","affiliation":[{"name":"From the Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1381"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11892-015-0652-z"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.2147\/OPTH.S74959"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2015.04.003"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00417-014-2589-3"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1621\/nrs.07003"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.07.035"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1504387112"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2010.21"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.30582"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3291"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/274726"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1203\/PDR.0b013e3181d01a36"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20110462"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2008.05.007"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2015.06.003"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/705783"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.2611"},{"key":"e_1_3_3_20_2","first-page":"290","article-title":"Roles of vascular endothelial growth factor and astrocyte degeneration in the genesis of retinopathy of prematurity.","volume":"37","author":"Stone J","year":"1996","unstructured":"Stone J, Chan-Ling T, Pe\u2019er J, Itin A, Gnessin H, Keshet E. 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