Factor-H-related protein 1 (FHR1), a promotor of para-inflammation in age-related macular degeneration
Summary
Age-related macular degeneration (AMD), a multifactorial type of retinal degeneration represents the most common cause for blindness in elderly. 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 Ca2+-signals and gene expression in both human RPE cell line and in vivo where muFHR1 affects Emr1+ 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. © 2025. The Author(s).
| Authors | Sekulic A, Herr SM, Mulfaul K, Pompös IM, Winkler S, Dietrich C, Obermayer B, Mullins RF, Conrad T, Zipfel PF, Sennlaub F, Skerka C, Strauß O |
|---|---|
| Journal | Journal of neuroinflammation |
| Publication Date | 2025 Jul 3;22(1):173 |
| PubMed | 40611130 |
| PubMed Central | PMC12226897 |
| DOI | 10.1186/s12974-025-03499-z |