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We found that multiple complement components were markedly up-regulated in retinas with human RP and the rd10 mouse model, coinciding spatiotemporally with photoreceptor degeneration, with increased C3 expression and activation localizing to activated retinal microglia. Genetic ablation of C3 accelerated structural and functional photoreceptor degeneration and altered retinal inflammatory gene expression. These phenotypes were recapitulated by genetic deletion of CR3, a microglia-expressed receptor for the C3 activation product iC3b, implicating C3-CR3 signaling as a regulator of microglia\u2013photoreceptor interactions. Deficiency of C3 or CR3 decreased microglial phagocytosis of apoptotic photoreceptors and increased microglial neurotoxicity to photoreceptors, demonstrating a novel adaptive role for complement-mediated microglial clearance of apoptotic photoreceptors in RP. These homeostatic neuroinflammatory mechanisms are relevant to the design and interpretation of immunomodulatory therapeutic approaches to retinal degenerative disease.<\/jats:p>","DOI":"10.1084\/jem.20190009","type":"journal-article","created":{"date-parts":[[2019,6,17]],"date-time":"2019-06-17T14:55:11Z","timestamp":1560783311000},"page":"1925-1943","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":109,"title":["C3- and CR3-dependent microglial clearance protects photoreceptors in retinitis pigmentosa"],"prefix":"10.1084","volume":"216","author":[{"given":"Sean M.","family":"Silverman","sequence":"first","affiliation":[{"name":"Section on Neuron-Glia Interactions in Retinal Disease, National Eye Institute, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8396-6625","authenticated-orcid":true,"given":"Wenxin","family":"Ma","sequence":"additional","affiliation":[{"name":"Section on Neuron-Glia Interactions in Retinal Disease, National Eye Institute, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Wang","sequence":"additional","affiliation":[{"name":"Section on Neuron-Glia Interactions in Retinal Disease, National Eye Institute, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0120-1969","authenticated-orcid":true,"given":"Lian","family":"Zhao","sequence":"additional","affiliation":[{"name":"Section on Neuron-Glia Interactions in Retinal Disease, National Eye Institute, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0681-4016","authenticated-orcid":true,"given":"Wai T.","family":"Wong","sequence":"additional","affiliation":[{"name":"Section on Neuron-Glia Interactions in Retinal Disease, National Eye Institute, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2019,6,17]]},"reference":[{"key":"2023072604551153600_bib1","doi-asserted-by":"publisher","first-page":"16426","DOI":"10.1073\/pnas.1311261110","article-title":"Structural insight on the recognition of surface-bound opsonins by the integrin I domain of complement receptor 3","volume":"110","author":"Bajic","year":"2013","journal-title":"Proc. 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