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Review
. 2015 Feb 10:8:7-18.
doi: 10.4137/IJTR.S19985. eCollection 2015.

The aryl hydrocarbon receptor: a review of its role in the physiology and pathology of the integument and its relationship to the tryptophan metabolism

Rowland Noakes  1
Affiliations
Review

The aryl hydrocarbon receptor: a review of its role in the physiology and pathology of the integument and its relationship to the tryptophan metabolism

Rowland Noakes. Int J Tryptophan Res. .

Abstract

The aryl hydrocarbon receptor (AHR) is a cytosolic receptor for low molecular weight molecules, of which the most widely recognized ligand is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and the most widely recognized effect, chloracne. Adverse effects of manipulation were most recently and graphically demonstrated by the poisoning of Viktor Yushchenko during the Ukrainian presidential elections of 2004. However, recent research has revealed a receptor with wide-ranging, and at times, paradoxical actions. It was arguably among the first biological receptors to be utilized by dermatologists, dating from the time of topical tar preparations as a therapeutic agent. I provide a review outlining the role AHR plays in the development, cellular oxidation/antioxidation, responses to ultraviolet light, melanogenesis, epidermal barrier function, and immune regulation and its relationship to tryptophan metabolism. Finally, I will review the role of AHR in diseases of the integument.

Keywords: Aryl hydrocarbon receptor; UV exposure; cellular oxidation/antioxidation; epidermal barrier; immune regulation; melanogenesis; tryptophan metabolism.

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Figures

Figure 1
Figure 1
In the cytosol, AHR exists in a latent state as part of a multiprotein complex. Chaperoning proteins includes heat shock protein 90 (hsp90), hsp23, and hepatitis B virus X-associated protein 2 (XAP2). On ligand binding, pp60src is released and binds to the epidermal growth factor receptor (EGFR), initiating MAPK signaling. The remainder of the complex translocates to the nucleus where it binds to the aryl hydrocarbon receptor nuclear transporter (ARNT), promoting the transcription of genes with xenobiotic response elements (XRE) in their promoters. Crosstalk occurs with the estrogen receptor (ER), retinoblastoma protein (Rb), retinoic acid (Reti), and NF-κB pathways. Control is provided by two loops, exportation of the AHR to the cytoplasm with subsequent degradation and transcription of the aryl hydrocarbon receptor repressor (AHRR).
Figure 2
Figure 2
The kynurenine pathway (Reproduced from Noakes, RR, Int. J. Tryptophan Res. 2013;6:67–71).
Figure 3
Figure 3
Stylized image of the skin. Notes: The epidermis consists mainly of keratinocytes (gray), which are continually generated from a basal layer and are progressively compacted as they migrate toward the stratum corneum from which they are shed. The epidermis also contains specialized antigen-presenting cells, Langerhans cells (red), and pigment-producing melanocytes (brown). The dermis provides mechanical strength and principally comprises collagen, elastin, and glycosaminoglycans. Cells found within the dermis include fibroblasts (brown), dermal dendrocytes (yellow), and mast cells (green). The panniculus (yellow) lies below the dermis. Appendegeal structures include pilosebaceous units comprising a hair follicle (filled brown), sebaceous glands (filled yellow), and a bulge area from which regeneration of the follicle occurs (filled gray). Sweat is produced by eccrine glands comprising a coil (filled green) and a duct.
Figure 4
Figure 4
Proposed pathogenesis of chloracne. Ligand binding to the AHR leads to nrf-2-mediated expression of Epgn, Slpi, and Sprr2d. This causes infundibular hyperkeratosis and obstruction of the pilosebaceous unit. With the progress of time, the sebaceous gland undergoes atrophy and a MADISH is formed.
Figure 5
Figure 5
Proposed involvement of the AHR in the pathogenesis of psoriasis. Enhanced TH 17 responsiveness to bacterial antigens likely explains the guttate variant seen after streptococcal infections. The sebo-psoriatic and flexural variants are probably due to enhanced responsiveness to Malassezia and Candida sp., respectively.
Figure 6
Figure 6
Proposed involvement of the AHR in scleroderma. A complex interplay involving anti-endothelial and fibrillin-1 antibodies, enhanced TH 17 responsiveness, and kynurenine metabolites are likely to be involved. AHR is involved in the mediation of several of these processes.
Figure 7
Figure 7
Proposed involvement of AHR in the pathogenesis of vitiligo. TH 17-mediated autoimmunity and a reduced capacity of melanocytes to manage oxidative stress are AHR mediated.
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