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Polymorphisms in complement factor-H increase, while absence of factor-H-related protein-1 (FHR1) decreases the AMD risk, currently explained by their opposing relationship. Here we identify a FHR1-driven pathway fostering chronic cellular inflammation. FHR1 accumulates below the retinal pigment epithelium (RPE) in AMD donor tissue and similarly the murine homolog, muFHR1 is abundant in three AMD-relevant mouse models. These mouse models express the muFHR1 receptor EGF-like module-containing mucin-like hormone receptor 1 (Emr1) on the RPE and on invading mononuclear phagocytes (MP), where both cells form clusters via muFHR1\/Emr1. FHR1 ignited EMR2-dependent Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -signals and gene expression in both human RPE cell line and in vivo where muFHR1 affects Emr1\n                    <jats:sup>+<\/jats:sup>\n                    cells (RPE and MP) gene expression shown by RNAseq analysis. As muFHR1 deletion in mice revealed significantly reduced MP invasion and neoangiogenesis in laser-induced choroidal neovascularization, we hypothesize that FHR1 accumulates, stabilizes and activates MP in the stage of RPE degeneration.\n                  <\/jats:p>","DOI":"10.1186\/s12974-025-03499-z","type":"journal-article","created":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T13:10:58Z","timestamp":1751548258000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Factor-H-related protein 1 (FHR1), a promotor of para-inflammation in age-related macular degeneration"],"prefix":"10.1186","volume":"22","author":[{"given":"Andjela","family":"Sekulic","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah M.","family":"Herr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Mulfaul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inga-Marie","family":"Pomp\u00f6s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Winkler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carola","family":"Dietrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedikt","family":"Obermayer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert F.","family":"Mullins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Conrad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter F.","family":"Zipfel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Sennlaub","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Skerka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olaf","family":"Strau\u00df","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,3]]},"reference":[{"key":"3499_CR1","doi-asserted-by":"crossref","unstructured":"Chirco KR, Sohn EH, Stone EM, Tucker BA, Mullins RF. 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After obtaining informed consent, patients\u2019 data, blood and tissue samples were collected according to the guidelines of the local ethics committees (EA2\/004\/14) and according to the Guidelines of the World Medical Association Declaration of Helsinki. All animal procedures used in this study were carried out in accordance relevant guideline and regulations according to the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and approved by the Landesamt f\u00fcr Gesundheit und Soziales, LageSo, Berlin; Licenses\u2013 T-CH 0027\/20 and G0005\/21 and \u201cComit\u00e9 d\u2019\u00e9thique en exp\u00e9rimentation animale Charles Darwin\u201d (Ce5\/2010\/013; Ce5\/2011\/033; Ce5\/2010\/044). All methods are reported with ARRIVE guidelines.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"PFZ received honoraria and speaker fees from Alexion, Alnylam, Bayer, CSL Vifor, Eleva Biologics, Novartis and Samsung Bioepis. CS consulted for ELEVA and received compensation and OS received lecture fees from Bayer AG.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"173"}}