Apolipoprotein E promotes subretinal mononuclear phagocyte survival

Abstract

Purpose: Physiologically, the retinal pigment epithelium (RPE) expresses immunosuppressive signals such as FAS ligand (FASL), which prevents the accumulation of leukocytes in the subretinal space. Age related macular degeneration (AMD) is associated with a breakdown of the subretinal immunosuppressive environment and chronic accumulation of mononuclear phagocytes (MPs). MPs are known to express high levels of Apolipoprotein E (APOE) and the APOE isoform 2, which is associated with higher APOE concentrations, increases the risk of AMD. Here we investigated the influence of APOE on subretinal MP accumulation.

Methods: This study used wildtype-, Cx3cr1^G/G-, ApoE^-/--, Cx3cr1^G/GApoE^-/--, Fas^lpr-, and FasL^gld-mice, recombinant APOE, IL6, IL-6 blocking antibody and a Fas agonist. The subretinal MP accumulation was studied in age-, light-, and-laser-induced subretinal inflammation and subretinal adaptive transfer of MPs of the different genotypes to wildtype mice.

Results: We show that subretinal MPs in AMD patients accumulate on the RPE and express high levels of APOE. MPs of Cx3cr1^-/-mice that develop MP accumulation on the RPE, photoreceptor degeneration, and increased choroidal neovascularization, similarly express high levels of APOE. ApoE deletion in Cx3cr1^-/-mice prevents pathogenic age- and stress-induced subretinal MP accumulation. We demonstrate that increased APOE levels induce IL-6 in MPs via the activation of the TLR2-CD14-dependent innate immunity receptor cluster. IL-6 in turn represses RPE FasL expression and prolongs subretinal MP survival. This mechanism may account, in part, for the MP accumulation observed in Cx3cr1^-/-mice.

Conclusions: Our results underline the inflammatory role of APOE in sterile inflammation in the immunosuppressive subretinal space. They provide rationale for the implication of the APOE2 isoform and IL-6 in AMD, and open avenues toward therapies inhibiting pathogenic chronic inflammation in late AMD.