Complement Factor H Inhibits CD47-Mediated Resolution of Inflammation

Variants of the CFH gene, encoding complement factor H (CFH), show strong association with age-related macular degeneration (AMD), a major cause of blindness. Here, we used murine models of AMD to examine the contribution of CFH to disease etiology. Cfh deletion protected the mice from the pathogenic subretinal accumulation of mononuclear phagocytes (MP) that characterize AMD and showed accelerated resolution of inflammation. MP persistence arose secondary to binding of CFH to CD11b, which obstructed the homeostatic elimination of MPs from the subretinal space mediated by thrombospsondin-1 (TSP-1) activation of CD47. The AMD-associated CFH(H402) variant markedly increased this inhibitory effect on microglial cells, supporting a causal link to disease etiology. This mechanism is not restricted to the eye, as similar results were observed in a model of acute sterile peritonitis. Pharmacological activation of CD47 accelerated resolution of both subretinal and peritoneal inflammation, with implications for the treatment of chronic inflammatory disease. [Display omitted] •CFH deficiency restricts chronic subretinal mononuclear phagocyte accumulation•In inflammation resolution, MPs are eliminated via a CD47-dependent mechanism•CFH binding to integrin CD11b curbs TSP-1 activation of integrin-associated CD47•The AMD-associated CFH variant CFH(H402) potently inhibits microglial cell elimination Variants in complement factor H (CFH) show strong association to age-related macular degeneration. Calippe et al. find that CFH binding to mononuclear phagocytes (MP) curbs the CD47-mediated elimination of MPs that maintains homeostasis in the subretinal space. The AMD-associated CFH variant CFH(H402) increases subretinal MP accumulation, providing insight into disease etiology.