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Review
. 2020 Sep 16;21(18):6777.
doi: 10.3390/ijms21186777.

The Aryl Hydrocarbon Receptor: A Mediator and Potential Therapeutic Target for Ocular and Non-Ocular Neurodegenerative Diseases

Mayur Choudhary  1 , Goldis Malek  1   2
Affiliations
Review

The Aryl Hydrocarbon Receptor: A Mediator and Potential Therapeutic Target for Ocular and Non-Ocular Neurodegenerative Diseases

Mayur Choudhary et al. Int J Mol Sci. .

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor, which senses environmental, dietary or metabolic signals to mount a transcriptional response, vital in health and disease. As environmental stimuli and metabolic products have been shown to impact the central nervous system (CNS), a burgeoning area of research has been on the role of the AHR in ocular and non-ocular neurodegenerative diseases. Herein, we summarize our current knowledge, of AHR-controlled cellular processes and their impact on regulating pathobiology of select ocular and neurodegenerative diseases. We catalogue animal models generated to study the role of the AHR in tissue homeostasis and disease pathogenesis. Finally, we discuss the potential of targeting the AHR pathway as a therapeutic strategy, in the context of the maladies of the eye and brain.

Keywords: aryl hydrocarbon receptor; inflammation; neurodegeneration; retinal diseases; transcription factor.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The AHR signaling pathway. In the classical pathway, an inactive form of the AHR is cytoplasmic and complexed with HSP90, AIP and SRC. Upon ligand binding, the AHR complex translocates to the nucleus, where the AHR forms a complex with ARNT and binds to XRE, inducing AHR-target gene expression. The AHR can also induce transcription of genes involved in inflammation, immune response and/or development. AHRR competes with the AHR for binding with ARNT and forms the inactive heterodimer AHRR-ARNT. The dissociation of the AHR transcriptional complex leads to translocation of the AHR to the cytoplasm, where it is degraded via the proteasomal pathway. AHR: aryl hydrocarbon receptor; AHRR: AHR repressor; ARNT: AHR nuclear translocator; AIP: AHR-interacting protein; Ub: ubiquitin; and XRE: xenobiotic response element.
Figure 2
Figure 2
The AHR and neurodegeneration. AHR signaling is involved in the regulation of inflammation, neurotoxicity, and immune cell recruitment in various neurodegenerative diseases. The AHR regulates disease pathology via microglia and astrocytes in CNS. AHR agonists (endogenous and pharmacological) have been shown to inhibit NF-κB-mediated inflammatory signaling. EAE: experimental autoimmune encephalomyelitis; MS: multiple sclerosis; AD: Alzheimer’s disease.
Figure 3
Figure 3
The AHR and ocular pathologies. AHR signaling is involved in the regulation of numerous pathogenic pathways in ocular diseases, such as the dry and wet clinical subtypes of age-related macular degeneration (AMD) and uveitis. Much of the ocular pathologies known to be regulated by the AHR were discovered by careful characterization of the ocular phenotype of Ahr−/− mice. Notable pathogenic pathways in AMD include inflammation, angiogenesis, and lipid metabolism. AHR agonists have been shown to inhibit vascular leakage, apoptosis, inflammation and accumulation of sub-retinal immune cells. Treatment with AHR agonists has been shown to have a therapeutic effect in protecting RPE cells from lipid peroxidation-induced toxicities, choroidal neovascularization, and uveitis. Primary open-angle glaucoma and primary congenital glaucoma have been shown to be associated with polymorphisms in AHR target genes cytochrome p450 A1 and B1 (CYP1A1 and CYP1B1). Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) have been shown to be associated with mutations in AHR as well as AIPL1. AIPL1: Aryl-hydrocarbon-interacting protein-like 1; 4HNE: 4-hydroxynonenal; CNV: choroidal neovascularization; AMD: age-related macular degeneration; OS: photoreceptor outer segments; RPE: retinal pigment epithelium; BrM: Bruch’s membrane.
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