Aryl hydrocarbon receptor deficiency causes dysregulated cellular matrix metabolism and age-related macular degeneration-like pathology

Abstract

The aryl hydrocarbon receptor (AhR) is a nuclear receptor that regulates xenobiotic metabolism and detoxification. Herein, we report a previously undescribed role for the AhR signaling pathway as an essential defense mechanism in the pathogenesis of early dry age-related macular degeneration (AMD), the leading cause of vision loss in the elderly. We found that AhR activity and protein levels in human retinal pigment epithelial (RPE) cells, cells vulnerable in AMD, decrease with age. This finding is significant given that age is the most established risk factor for development of AMD. Moreover, AhR −/− mice exhibit decreased visual function and develop dry AMD-like pathology, including disrupted RPE cell tight junctions, accumulation of RPE cell lipofuscin, basal laminar and linear-like deposit material, Bruch's membrane thickening, and progressive RPE and choroidal atrophy. High-serum low-density lipoprotein levels were also observed in AhR −/− mice. In its oxidized form, this lipoprotein can stimulate increased secretion of extracellular matrix molecules commonly found in deposits from RPE cells, in an AhR-dependent manner. This study demonstrates the importance of cellular clearance via the AhR signaling pathway in dry AMD pathogenesis, implicating AhR as a potential target, and the mouse model as a useful platform for validating future therapies.retinal pigment epithelium | retinal disease | toxin metabolism | oxidized low density lipoprotein A ge-related macular degeneration (AMD) is the leading cause of vision loss in individuals over the age of 55 y in the Western world (1). It is a complex and heterogeneous disease, multifactorial with genetic, systemic health, and environmental factors regulating its initiation and progression (2, 3). Phenotypically, eyes with the dry clinical subtype are characterized by accumulation of focal and diffuse extracellular lipid protein-rich deposits below the retinal pigment epithelial cells (sub-RPE in 85-87% of cases) and/or within Bruch's membrane. These deposits include drusen, basal laminar, and basal linear deposits (4, 5) and are associated with RPE dysfunction, apoptosis, and ultimately degeneration. The latter of which, RPE atrophy and degeneration, is seen in an advanced form of dry AMD called geographic atrophy. Currently, there are no treatment options available for these patients. Despite advances in our understanding of the composition of sub-RPE deposits (6-8), the critical molecular events and signaling pathways leading to progressive RPE dysfunction and extracellular deposit biogenesis are still unknown.

The Project MACULA Retinal Pigment Epithelium Grading System for Histology and Optical Coherence Tomography in Age-Related Macular Degeneration

“…17,[72][73][74] Investigators using single-section TEM to visualize these cells in experimental thermal injury and retinal detachment considered them RPEderived because of numerous intracellular granules non-delimited by a phagosome membrane, abundant smooth endoplasmic reticulum, and loss of apical microvilli and junctional complexes in transitioning to non-epithelial. [75][76][77][78] Recent evidence indicates that numerous Iba-1-immunoreactive microglia reside in the subretinal space of aged mice [79][80][81][82][83][84][85] and appear also in human retinal degenerations including AMD. 79,86,87 Our technique was not optimized for detecting widely scattered, small-body microglia, although we certainly sought such cells, as they can be recognized without selective labels.…”

Glia–neuron interactions in the mammalian retina

“…The AhR (a nuclear aryl hydrocarbon receptor) signalling pathway is a defence mechanism that detoxifies metabolic waste molecules and xenobiotics, and its activity in human RPE cells diminishes with age (Hu et al, 2013). A knock-out mouse model deficient in AhR (Ahr À/À ) exhibits phenotypic characteristics of AMD, indicating that this signalling pathway may hinder the appearance of AMD (Hu et al, 2013;Kim et al, 2014). Accordingly, a complex collaboration of mechanisms dependent on immune competent cells and RPE cells appears to be responsible for the initiation and progression of AMD.…”

Emerging roles for nuclear receptors in the pathogenesis of age-related macular degeneration

“…This is best illustrated by reviewing data from a haplotype analysis of AMD versus control cases that concluded the aryl hydrocarbon receptor ( AhR ), a receptor critical in the biological response to endogenous and xenobiotic toxins, may be associated with the development of AMD [163]. Though a significant difference in expression was not seen, this minor genetic association along with the overlap between molecular events regulated by AhR, such as toxin clearance, extracellular matrix proteolysis, cellular degradation, and events important in AMD, led to the hypothesis that the AhR-signaling pathway may be important in AMD pathogenesis and would need to be investigated in detail using both in vitro and in vivo methods [164]. In fact, in vitro, evaluation of the activity of AhR in primary cultures of young and old human RPE cells found a significant decrease as a function of age, suggesting that the RPE cells ability to clear toxin and “garbage” becomes less efficient with age.…”