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M\u00fcller cells are key components of the retinal neurovascular unit and diabetes has a detrimental impact on these glial cells, triggering progressive neurovascular pathology of DR. Amongst many factors expressed by M\u00fcller cells, interleukin-33 (IL-33) has an established immunomodulatory role, and we investigated the role of endogenous IL-33 in DR. The expression of IL-33 in M\u00fcller cells increased during diabetes. Wild-type and Il33\u2212\/\u2212 mice developed equivalent levels of hyperglycaemia and weight loss following streptozotocin-induced diabetes. Electroretinogram a- and b-wave amplitudes, neuroretina thickness, and the numbers of cone photoreceptors and ganglion cells were significantly reduced in Il33\u2212\/\u2212 diabetic mice compared with those in wild-type counterparts. The Il33\u2212\/\u2212 diabetic retina also exhibited microglial activation, sustained gliosis, and upregulation of pro-inflammatory cytokines and neurotrophins. Primary M\u00fcller cells from Il33\u2212\/\u2212 mice expressed significantly lower levels of neurotransmitter-related genes (Glul and Slc1a3) and neurotrophin genes (Cntf, Lif, Igf1 and Ngf) under high-glucose conditions. Our results suggest that deletion of IL-33 promotes inflammation and neurodegeneration in DR, and that this cytokine is critical for regulation of glutamate metabolism, neurotransmitter recycling and neurotrophin secretion by M\u00fcller cells.<\/jats:p>","DOI":"10.1242\/dmm.050174","type":"journal-article","created":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T03:40:10Z","timestamp":1693971610000},"source":"Crossref","is-referenced-by-count":28,"title":["IL-33 regulates M\u00fcller cell-mediated retinal inflammation and neurodegeneration in diabetic retinopathy"],"prefix":"10.1242","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5178-5029","authenticated-orcid":false,"given":"Josy","family":"Augustine","sequence":"first","affiliation":[{"name":"Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast , Belfast BT9 7BL, Northern Ireland , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1875-4236","authenticated-orcid":false,"given":"Sofia","family":"Pavlou","sequence":"additional","affiliation":[{"name":"Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast , Belfast BT9 7BL, Northern Ireland , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8076-178X","authenticated-orcid":false,"given":"Kevin","family":"Harkin","sequence":"additional","affiliation":[{"name":"Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast , Belfast BT9 7BL, Northern Ireland , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8647-9918","authenticated-orcid":false,"given":"Alan W.","family":"Stitt","sequence":"additional","affiliation":[{"name":"Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast , Belfast BT9 7BL, Northern Ireland , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4000-931X","authenticated-orcid":false,"given":"Heping","family":"Xu","sequence":"additional","affiliation":[{"name":"Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast , Belfast BT9 7BL, Northern Ireland , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5661-1386","authenticated-orcid":false,"given":"Mei","family":"Chen","sequence":"additional","affiliation":[{"name":"Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast , Belfast BT9 7BL, Northern Ireland , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2023,9,6]]},"reference":[{"key":"2023090607395169700_DMM050174C1","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1038\/s41598-022-05284-x","article-title":"High glucose concentrations induce oxidative stress by inhibiting Nrf2 expression in rat M\u00fcller retinal cells in vitro","volume":"12","author":"Albert-Garay","year":"2022","journal-title":"Sci. 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