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

Abstract

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.

Keywords: age related macular degeneration (AMD); dendritic cell; inflammation; macrophage; microglia; mononuclear phagocyte (MP); para-inflammation; retinal pigment epithelium (RPE).

FIGURE 1

Schematic of changes that occur in the eye of age-related macular degeneration (AMD) patients. (A) Schematic render of the eye showing posterior ocular tissues affected in AMD, expanded in subsequent panels. (B) Healthy posterior eye, showing transverse section of the retinal layers, the retinal pigment epithelium (RPE), Bruch’s membrane (BM), and vascular supply (the choriocapillaris, CC). The location of the mononuclear phagocytes (MPs) is indicated including retinal tissue resident microglia associated with the neuronal synaptic layers (nerve fiber layer MPs not shown) and MPs in the choroid, including dendritic cells, macrophages and other monocytes. (C) Schematic of early/intermediate AMD showing thickening of BM, deposition of extracellular waste around the RPE (drusen and reticular pseudodrusen, RPD), thinned choroid, and changes in MPs, including activation of microglia within the retina. (D) Schematic of late-stage AMD, geographic atrophy, showing loss of photoreceptors and RPE cells, thinning of BM in regions of cell loss, and deposition of large drusen. Microglia within the retina are activated and activated macrophages on the choroidal side are associated with the damaged basal RPE/BM. (E) Schematic of late-stage neovascular AMD showing choroidal neovascularization (CNV), loss of photoreceptors and RPE cells, thinning of BM in regions of cell loss and deposition of large drusen. Microglia within the retina are activated and peripheral circulating monocytes and dendritic cells are activated and associated with damaged RPE and are also able to enter the retina via new leaky vessels. This illustration was started from a BioRender Template and content and stylistic modifications were made.

FIGURE 2

Schematic of changes that occur in the retinal pigment epithelium (RPE) of age-related macular degeneration (AMD) patients. (A) Schematic of changes within the RPE in late-stage AMD, including weakening of tight junctions that form the blood retinal barrier, deposition of lipofuscin and enlarged failed lysosomes. Deposition of extracellular waste around the RPE, large drusen on the basal side of the RPE are apparent and reticular pseudodrusen (RPD) on the apical side may also manifest. (B) Schematic showing changes in the tight junctions of the RPE in AMD in flat mount view. Healthy RPE are hexagonal in shape and tight junctions form a continuous connection around each RPE cell. In AMD, RPE cells may be larger due to cell loss and tight junctions may be separated, thinned, thickened, split or fragmented, modified from Ach et al. (2015). (C) Example of the effects of aging on the mouse RPE. Tight junction ZO-1 labeling of young (3 month) and old (22 month) mouse RPE, shows increased RPE cell size in the aged tissue, suggesting cell loss with age. Some of this illustration was started from a BioRender Template and content and stylistic modifications were made.

FIGURE 3

Schematic of mononuclear phagocyte (MP) interactions with the ocular tissues in health eyes and late-stage age-related macular degeneration (AMD). (A) Healthy posterior eye, showing transverse section of the retinal layers, the retinal pigment epithelium (RPE), Bruch’s membrane (BM), and vascular supply (the choriocapillaris, CC). The location of the mononuclear phagocytes (MPs) is indicated including retinal tissue resident microglia associated with the neuronal synaptic layers (nerve fiber layer MPs not shown) and MPs in the choroid, including dendritic cells, macrophages and other monocytes. RPE expression of immunosuppressive cytokines (e.g., IL-10), growth factors (e.g., PEDF) and immune factors (e.g., CFH) are shown. (B) Schematic of late-stage AMD, geographic atrophy, showing loss of photoreceptors and RPE cells, and deposition of large drusen. The RPE expresses chemokines, e.g., CCL-2 and IL-8 to recruit immune cells to areas of damage. Microglia within the retina are activated, recruited to damaged RPE cells and RPD and activated iNOS-positive macrophages on the choroidal side are associated with the damaged RPE and drusen containing immunogenic complement pathway factors. Activated MP interaction with the RPE can contribute to RPE dysfunction and apoptosis. (C) Schematic of late-stage neovascular AMD showing choroidal neovascularization (CNV), loss of photoreceptors and RPE cells, and deposition of large drusen. Microglia within the retina are activated. Peripheral circulating MPs, dendritic cells are activated and associated with damaged RPE releasing VEGF and MMP-9 to drive new vessel development and are also able to enter the retina via new leaky vessels. There is an increase in expression of pro-inflammatory chemokines and cytokines by MPs and the RPE which drives angiogenesis and contributes to RPE cell dysfunction and death. Some of this illustration was started from a BioRender Template and content and stylistic modifications were made.