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Here, we examined the mechanisms that underlie macrophage-driven retinal cell death. Monocytes were extracted from patients with AMD and differentiated into macrophages (hMd\u0278s), which were characterized based on proteomics, gene expression, and ex vivo and in vivo properties. Using bioinformatics, we identified the signaling pathway involved in macrophage-driven retinal cell death, and we assessed the therapeutic potential of targeting this pathway. We found that M2a hMd\u0278s were associated with retinal cell death in retinal explants and following adoptive transfer in a photic injury model. Moreover, M2a hMd\u0278s express several CCRI (C-C chemokine receptor type 1) ligands. Importantly, CCR1 was upregulated in M\u00fcller cells in models of retinal injury and aging, and CCR1 expression was correlated with retinal damage. Lastly, inhibiting CCR1 reduced photic-induced retinal damage, photoreceptor cell apoptosis, and retinal inflammation. These data suggest that hMd\u0278s, CCR1, and M\u00fcller cells work together to drive retinal and macular degeneration, suggesting that CCR1 may serve as a target for treating these sight-threatening conditions.<\/jats:p>","DOI":"10.7554\/elife.81208","type":"journal-article","created":{"date-parts":[[2023,10,5]],"date-time":"2023-10-05T07:15:11Z","timestamp":1696490111000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.81208","source":"Crossref","is-referenced-by-count":8,"title":["CCR1 mediates M\u00fcller cell activation and photoreceptor cell death in macular and retinal degeneration"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-8605-5775","authenticated-orcid":true,"given":"Sarah","family":"Elbaz-Hayoun","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01cqmqj90","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem","place":["Jerusalem, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Batya","family":"Rinsky","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01cqmqj90","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem","place":["Jerusalem, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2891-0079","authenticated-orcid":true,"given":"Shira","family":"Hagbi-Levi","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01cqmqj90","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem","place":["Jerusalem, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3155-2858","authenticated-orcid":true,"given":"Michelle","family":"Grunin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01cqmqj90","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem","place":["Jerusalem, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1897-4973","authenticated-orcid":true,"given":"Itay","family":"Chowers","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01cqmqj90","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Ophthalmology, Hadassah Medical Center, Faculty of Medicine, The Hebrew University of Jerusalem","place":["Jerusalem, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2023,10,30]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"261","DOI":"10.2337\/dbi16-0047","article-title":"M\u00fcller cell-microglia cross talk drives neuroinflammation in diabetic retinopathy","volume":"66","author":"Abcouwer","year":"2017","journal-title":"Diabetes"},{"key":"bib2","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/7901270","article-title":"Central role of oxidative stress in age-related macular degeneration: Evidence from a review of the molecular mechanisms and animal models","volume":"2020","author":"Abokyi","year":"2020","journal-title":"Oxidative Medicine and Cellular Longevity"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1016\/s0197-2456(99)00031-8","article-title":"The Age-Related Eye Disease Study (AREDS): design implications. 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