{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T14:08:26Z","timestamp":1793110106617,"version":"4.5.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,6,24]],"date-time":"2024-06-24T00:00:00Z","timestamp":1719187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>This study revealed a core regulator and common upstream mechanisms for the multifaceted pathological processes of age-related macular degeneration (AMD) and provided proof-of-concept for this new therapeutic target.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Comprehensive gene expression analysis was performed using RNA sequencing of eye cup from old mice as well as laser-induced choroidal neovascularization (CNV) mouse model. Through integrative analysis and protein-protein interaction (PPI) analysis, common pathways and key transcription factor was identified simultaneously engaged in age-related retinal degeneration and CNV, the two typical pathological process of AMD. Subsequently, the expression changes of <jats:italic>Spi1<\/jats:italic>, the key regulator, as well as the alternation of the downstream mechanisms were validated in both models through qRT-PCR, Elisa, flow cytometry and immunofluorescence. Further, we assessed the impact of <jats:italic>Spi1<\/jats:italic> knockdown <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> using gene intervention vectors carried by adeno-associated virus or lentivirus to test its potential as a therapeutic target.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Compared to corresponding controls, we found 1,939 and 1,319 genes differentially expressed in eye cups of old and CNV mice respectively. The integrative analysis identified a total of 275 overlapping DEGs, of which 150 genes were co-upregulated. PPI analysis verified a central transcription factor, SPI1. The significant upregulation of <jats:italic>Spi1<\/jats:italic> expression was then validated in both models, accompanied by macrophage polarization towards the M1 phenotype. Finally, SPI1 suppression significantly inhibited M1 polarization of BMDMs and attenuated neovascularization in CNV mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study demonstrates that SPI1 exerts a pivotal role in AMD by regulation of macrophage polarization and innate immune response, offering promise as an innovative target for treating AMD.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1421012","type":"journal-article","created":{"date-parts":[[2024,6,24]],"date-time":"2024-06-24T04:41:08Z","timestamp":1719204068000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["SPI1-mediated macrophage polarization aggravates age-related macular degeneration"],"prefix":"10.3389","volume":"15","author":[{"given":"Siyi","family":"Qi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingjie","family":"Kong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daode","family":"Bi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyu","family":"Kong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shujie","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,6,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.22608\/apo.2017251","article-title":"Updates on the epidemiology of age-related macular degeneration","volume":"6","author":"Jonas","year":"2017","journal-title":"Asia Pac J Ophthalmol (Phila)"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)61759-6","article-title":"Age-related macular degeneration","volume":"372","author":"Coleman","year":"2008","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)60282-7","article-title":"Age-related macular degeneration","volume":"379","author":"Lim","year":"2012","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S2214-109X(13)70145-1","article-title":"Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis","volume":"2","author":"Wong","year":"2014","journal-title":"Lancet Glob Health"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1996.03540140029022","article-title":"A prospective study of cigarette smoking and age-related macular degeneration in women","volume":"276","author":"Seddon","year":"1996","journal-title":"Jama"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1111\/joim.12227","article-title":"Is age-related macular degeneration a manifestation of systemic disease? 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