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Review
. 2022 Mar 3:4:791082.
doi: 10.3389/ftox.2022.791082. eCollection 2022.

More than Meets the Eye: The Aryl Hydrocarbon Receptor is an Environmental Sensor, Physiological Regulator and a Therapeutic Target in Ocular Disease

Christine L Hammond  1 , Elisa Roztocil  1 , Vardaan Gupta  1 , Steven E Feldon  1 , Collynn F Woeller  1   2
Affiliations
Review

More than Meets the Eye: The Aryl Hydrocarbon Receptor is an Environmental Sensor, Physiological Regulator and a Therapeutic Target in Ocular Disease

Christine L Hammond et al. Front Toxicol. .

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.

Keywords: 6-formylindolo (3, 2-b) carbazole; AHR (aryl hydrocarbon agonist); FICZ; TCDD (2, 8-tetrachlorodibenzo- p-dioxin); cigarette; eye; retina; thyroid eye disease (TED).

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The AHR and its cellular functions as a ligand-activated transcription factor and cytoplasmic modifier. (A) Modular diagram of the human AHR protein motifs showing relevant residue numbers (1–848). The AHR contains a basic helix-loop-helix (bHLH) DNA binding domain, a Per-Arnt-Sim (PAS) motif, which includes part of the ligand binding domain (LBD) and at the C-terminal region a transcriptional activation domain that includes a glutamine rich Q-rich) motif. (B) Without ligand, AHR is localized to the cytoplasm and bound to chaperone proteins AIP, HSP90 and p23. When and AHR ligands enters the cell, the AHR binds to the AHR nuclear translocator protein (ARNT) in the cytoplasm and is transported into the nucleus where it acts as a transcription factor. AHR-dependent genes include numerous cytochrome P450 enzymes, such as CYP1B1 and CYP1A1, which are involved in metabolism and clearance of xenobiotic polycyclic aromatic hydrocarbons (PAHs).
FIGURE 2
FIGURE 2
Diagram of the eye highlighting regions and cells that have been shown to express the AHR. The text in orange highlight indicates cells and tissue that express the AHR. The eye is a unique sensory organ, composed of three main layers. The outer layer is composed of the sclera and cornea, which are directly exposed to the environment on the surface of the eye. The middle layer is made up of the ciliary body, iris and choroid while the inner most layer is the retina. Other parts of the ocular system include the fluid filled vitreous in between the retina, and ciliary body and the lens. Orbital tissue behind the eye provides structural support and protects the optic nerve. Retinal pigment epithelial cells (RPE), choroid, the ciliary body and non-pigmented ciliary epithelial cells, orbital fibroblasts and the cornea have all been shown to express the AHR.
FIGURE 3
FIGURE 3
Summary of the role of AHR in eye disease and the therapeutic potential of AHR activation AHR. A summary of the role of AHR in development of eye disease (left side) as compartmentalized into Anterior, posterior and orbital sections of the ocular system. On the right side is a summary of the potential use of AHR ligands in treating ocular disease.
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