Complement factor H related protein 1 (FHR1): regulator of inflammation

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The so-called sterile inflammation is a central mechanism in degenerative diseases with large impact into public health such as age-related macular degeneration (AMD). As a basic mechanism, injured/necrotic cells or extracellular deposits trigger immune mechanisms, including cellular immune responses by mononuclear phagocytes. How this is induced is still not clear. The plasma protein Factor H related protein-1 (FHR1 in humans; FHRE in mice) recognizes these danger signals. FHR1 binds to damaged or degenerative surfaces and can then directly activate monocytes via plasma membrane receptors, CR3 and EMR2. Given these observations, we see a prominent role of FHR1 in chronic inflammatory degenerative diseases; her in AMD. We want to clarify how FHR1 binds to surfaces, activates receptors in the plasma membrane of immune competent cells, relates in plasma levels to diseases and participates in the chain of events leading to sterile inflammation and auto-inflammation in AMD. For translation, we will analyze human tissues with respect to FHR1 signaling. In preliminary studies, we found FHR1 present in Drusen in eyes of AMD patients, FHRE in mouse models for AMD. Therefore, we assume a new functional mechanism seen as FHR1-dependent inflammation in which monocytes and retinal cells with immune cell-like properties play an active role. This is supported by the fact that in AMD the chromosomal deletion of FHR1 is protective. For that reason, we aim to investigate the molecular role of FHR1 in inflammation in vitro and in vivo and expect to find a new treatment target in AMD.