Aging induces cell loss and a decline in phagosome processing in the mouse retinal pigment epithelium.

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss and dysfunction in the retinal pigment epithelium (RPE) with age is known to contribute to disease development. The aim of this study was to investigate how the C57BL/6J mouse RPE changes with age. RPE structure was found to change with age and eccentricity, with cell size increasing, nuclei lost, and tight junctions altered in the peripheral retina. Phagocytosis of photoreceptor outer segments (POS) by the RPE was investigated using gene expression analysis and histology. RNA-Seq transcriptomic gene profiling of the RPE showed a downregulation of genes involved in phagosome processing and histological analysis showed a decline in phagosome-lysosome association in the aged tissue. In addition, failures in the autophagy pathway that modulates intracellular waste degradation were observed in the aged RPE tissue. These findings highlight that RPE cell loss and slowing of POS processing contribute to RPE dysfunction with age and may predispose the aging eye to AMD development.

Exploring the pathogenesis of age-related macular degeneration: A review of the interplay between retinal pigment epithelium dysfunction and the innate immune system.

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in the older population. Classical hallmarks of early and intermediate AMD are accumulation of drusen, a waste deposit formed under the retina, and pigmentary abnormalities in the retinal pigment epithelium (RPE). When the disease progresses into late AMD, vision is affected due to death of the RPE and the light-sensitive photoreceptors. The RPE is essential to the health of the retina as it forms the outer blood retinal barrier, which establishes ocular immune regulation, and provides support for the photoreceptors. Due to its unique anatomical position, the RPE can communicate with the retinal environment and the systemic immune environment. In AMD, RPE dysfunction and the accumulation of drusen drive the infiltration of retinal and systemic innate immune cells into the outer retina. While recruited endogenous or systemic mononuclear phagocytes (MPs) contribute to the removal of noxious debris, the accumulation of MPs can also result in chronic inflammation and contribute to AMD progression. In addition, direct communication and indirect molecular signaling between MPs and the RPE may promote RPE cell death, choroidal neovascularization and fibrotic scarring that occur in late AMD. In this review, we explore how the RPE and innate immune cells maintain retinal homeostasis, and detail how RPE dysfunction and aberrant immune cell recruitment contribute to AMD pathogenesis. Evidence from AMD patients will be discussed in conjunction with data from preclinical models, to shed light on future therapeutic targets for the treatment of AMD.