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Interleukin-6 (IL6) is a pro-inflammatory and pro-angiogenic cytokine that is correlated with AMD progression and nAMD activity. We hypothesize that anti-IL6 therapy is a potential nAMD therapeutic. We found that IL6 levels were increased after laser injury and expressed by macrophages. <jats:italic>Il6<\/jats:italic>-deficiency decreased laser-induced CNV area and exogenous IL6 addition increased choroidal sprouting angiogenesis. <jats:italic>Il6<\/jats:italic>-null mice demonstrated equally increased macrophage numbers as wildtype mice. At steady state, IL6R expression was detected on peripheral blood and ocular monocytes. After laser injury, the number of IL6R<jats:sup>+<\/jats:sup>Ly6C<jats:sup>+<\/jats:sup> monocytes in blood and IL6R<jats:sup>+<\/jats:sup> macrophages in the eye were increased. In human choroid, macrophages expressed <jats:italic>IL6<\/jats:italic>, <jats:italic>IL6R<\/jats:italic>, and <jats:italic>IL6ST<\/jats:italic>. Furthermore, <jats:italic>IL6R<\/jats:italic><jats:sup>+<\/jats:sup> macrophages displayed a transcriptional profile consistent with STAT3 (signal transducer and activator of transcription 3) activation and angiogenesis. Our data show that IL6 is both necessary and sufficient for choroidal angiogenesis. Macrophage-derived IL6 may stimulate choroidal angiogenesis via classical activation of IL6R<jats:sup>+<\/jats:sup> macrophages, which then stimulate angiogenesis. Targeting IL6 or the IL6R could be an effective adjunctive therapy for treatment-resistant nAMD patients.<\/jats:p>","DOI":"10.1038\/s41598-021-97522-x","type":"journal-article","created":{"date-parts":[[2021,9,10]],"date-time":"2021-09-10T10:02:45Z","timestamp":1631268165000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Macrophage-derived interleukin-6 is necessary and sufficient for choroidal angiogenesis"],"prefix":"10.1038","volume":"11","author":[{"given":"Steven","family":"Droho","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla M.","family":"Cuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harris","family":"Perlman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy A.","family":"Lavine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,10]]},"reference":[{"key":"97522_CR1","doi-asserted-by":"publisher","first-page":"1432","DOI":"10.1056\/NEJMoa062655","volume":"355","author":"DM Brown","year":"2006","unstructured":"Brown, D. 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