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Recent evidence indicates the RPE acts as an adjacent lactate sink, suppressing glycolysis in the epithelium in order to maximize glycolysis in the photoreceptors. Dysregulated metabolism within the RPE has been implicated in the pathogenesis of age-related macular degeneration (AMD), a leading cause of vision loss. In the present study, we investigate the effects of four cytokines associated with AMD, TNF\u03b1, TGF-\u03b22, IL-6, and IL-1\u03b2, as well as a cocktail containing all four cytokines, on RPE metabolism using ARPE-19 cells, primary human RPE cells, and ex vivo rat eyecups. Strikingly, we found cytokine-specific changes in numerous metabolic markers including lactate production, glucose consumption, extracellular acidification rate, and oxygen consumption rate accompanied by increases in total mitochondrial volume and ATP production. Together, all four cytokines could potently override the constitutive suppression of glycolysis in the RPE, through a mechanism independent of PI3K\/AKT, MEK\/ERK, or NF-\u03baB. Finally, we observed changes in glycolytic gene expression with cytokine treatment, including in lactate dehydrogenase subunit and glucose transporter expression. Our findings provide new insights into the metabolic changes in the RPE under inflammatory conditions and highlight potential therapeutic targets for AMD.<\/jats:p>","DOI":"10.1042\/bsr20231904","type":"journal-article","created":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T05:00:51Z","timestamp":1712120451000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Metabolic reprogramming of the retinal pigment epithelium by cytokines associated with age-related macular degeneration"],"prefix":"10.1042","volume":"44","author":[{"given":"David\u00a0S.","family":"Hansman","sequence":"first","affiliation":[{"name":"1School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuefang","family":"Ma","sequence":"additional","affiliation":[{"name":"2College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Thomas","sequence":"additional","affiliation":[{"name":"3South Australian Health and Medical Research Institute (SAHMRI), Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justine\u00a0R.","family":"Smith","sequence":"additional","affiliation":[{"name":"2College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert\u00a0J.","family":"Casson","sequence":"additional","affiliation":[{"name":"4Discipline of Ophthalmology and Visual Science, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6085-8936","authenticated-orcid":false,"given":"Daniel\u00a0J.","family":"Peet","sequence":"additional","affiliation":[{"name":"1School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2024,4,16]]},"reference":[{"key":"2024041609454851100_B1","first-page":"309","article-title":"On the metabolism of carcinoma cells","volume":"152","author":"Warburg","year":"1924","journal-title":"Biochem. 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