Subretinal Mononuclear Phagocyte survival and accumulation in AMD

Abstract

AbstractThe subretinal space, located between the RPE and the photoreceptor outer segments, is a zone of immune privilege as a consequence of immunosuppressive RPE signals, possibly to limit or subvert inflammatory damage. Age related macular degeneration (AMD) is associated with a breakdown of the subretinal immunosuppressive environment and infiltration and activation of mononuclear phagocytes (MPs, a family of cells that include microglial cells, monocytes, and macrophages) in both late forms of AMD. The molecular mechanisms that provoke the breakdown of local immuno‐suppression in AMD are unknown. Our recent data indicates that Apolipoprotein E (APOE), a lipoprotein that exists in three isoforms in human, participates in this process. We demonstrate that increased APOE secretion from MPs, observed in MPs carrying the AMD‐associated APOe2 allele, leads to prolonged subretinal MP survival and accumulation. We show that subretinal MP accumulation in APOe2 mice is associated with photoreceptor degeneration and excessive experimentally induced choroidal neovascularization, major hallmarks of late AMD. Our results provide a molecular mechanism of local breakdown of immuno‐suppression rationale for the increased AMD‐risk of APOe2 carriers.