Abstract
The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor originally identified as an environmental sensor of xenobiotic chemicals. However, studies have revealed that the AHR regulates crucial aspects of cell growth and metabolism, development and the immune system. The importance of the AHR and AHR signaling in eye development, toxicology and disease is now being uncovered. The AHR is expressed in many ocular tissues including the retina, choroid, cornea and the orbit. A significant role for the AHR in age-related macular degeneration (AMD), autoimmune uveitis, and other ocular diseases has been identified. Ligands for the AHR are structurally diverse organic molecules from exogenous and endogenous sources. Natural AHR ligands include metabolites of tryptophan and byproducts of the microbiome. Xenobiotic AHR ligands include persistent environmental pollutants such as dioxins, benzo (a) pyrene [B (a) P] and polychlorinated biphenyls (PCBs). Pharmaceutical agents including the proton pump inhibitors, esomeprazole and lansoprazole, and the immunosuppressive drug, leflunomide, activate the AHR. In this review, we highlight the role of the AHR in the eye and discuss how AHR signaling is involved in responding to endogenous and environmental stimuli. We also present the emerging concept that the AHR is a promising therapeutic target for eye disease.
Highlights
One billion people in the world have a form of visual impairment (GBD 2019 Blindness and Vision Impairment Collaborators and Vision Loss Expert Group of the Global Burden of Disease Study, 2021)
These results suggest that the loss of aryl hydrocarbon receptor (AHR) expression or TCDD-induced activation of AHR contributes to angiogenesis, inflammation, and alterations in the extracellular matrix, all of which are observed in wet age-related macular degeneration (AMD)
While the AHR may have a role in regulating eye development, sensing environmental pollutants and ocular disease, several studies have revealed that activating the AHR using AHR ligands may be a novel mechanism to treat ocular diseases (Figure 3)
Summary
One billion people in the world have a form of visual impairment (GBD 2019 Blindness and Vision Impairment Collaborators and Vision Loss Expert Group of the Global Burden of Disease Study, 2021). The ocular surface is directly exposed to environmental pollutants, including cigarette smoke, biomass smoke from wood, coal or other organic material, and ambient particulate matter (Martin et al, 2013; Araj et al, 2020) These environmental components contain polycyclic aromatic hydrocarbons (PAHs) that can serve as ligands of the aryl hydrocarbon receptor (AHR), such as benzo (a) pyrene [B (a) P], dioxins, and hydroquinone (Hu et al, 2013; Julliard et al, 2014; Awji et al, 2015). Ligand-mediated activation of the AHR can mitigate chronic inflammation, including inflammation due to chronic smoke exposure (Baglole et al, 2008; Sarill et al, 2015; Rogers et al, 2017) This dichotomy in the role of the AHR may be due to differences in ligand half-life, binding affinity, timing of activation, cell type, and interactions with other signaling pathways. We highlight the role of the AHR in the ocular system, as an environmental sensor, normal physiological regulator and potential therapeutic target
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