Abstract
Aryl hydrocarbon receptor (AHR) is an important regulator of skin barrier function. It also controls immune-mediated skin responses. The AHR modulates various physiological functions by acting as a sensor that mediates environment–cell interactions, particularly during immune and inflammatory responses. Diverse experimental systems have been used to assess the AHR’s role in skin inflammation, including in vitro assays of keratinocyte stimulation and murine models of psoriasis and atopic dermatitis. Similar approaches have addressed the role of AHR ligands, e.g., TCDD, FICZ, and microbiota-derived metabolites, in skin homeostasis and pathology. Tapinarof is a novel AHR-modulating agent that inhibits skin inflammation and enhances skin barrier function. The topical application of tapinarof is being evaluated in clinical trials to treat psoriasis and atopic dermatitis. In the present review, we summarize the effects of natural and synthetic AHR ligands in keratinocytes and inflammatory cells, and their relevance in normal skin homeostasis and cutaneous inflammatory diseases.
Highlights
Most of the non-conserved changes of the Aryl hydrocarbon receptor (AHR) are found in the transcriptional activation domain (TAD), resulting in differential protein–protein interactions with other coactivators, corepressors, or nuclear receptors, which may result in differential gene expression regulation [24]
AHR activation leads to epigenetic changes in the FoxP3 locus, and the expression of additional transcription factors required for the induction of functional FoxP3+ Treg cells, such as decapentaplegic homolog (Smad)1 and Aiolos [73,74,75] (Figure 2)
Using the model of IL-23-induced skin inflammation, we demonstrated that CD69 expression controls AHR-mediated IL-22 expression in Th17 and γδ T cells [78]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The process of terminal keratinocyte differentiation involves the upregulated expression of specific proteins such as involucrin (IVL), loricrin (LOR), and filaggrin (FLG). AD and PS are frequent inflammatory cutaneous disorders, in which deregulation of immune cells is accompanied by alterations in keratinocyte differentiation, proliferation and overall barrier function [2,3]. IL-17-secreting cells, activated by elevated levels of IL-23 [2] They are treatable using biological therapies aimed at blocking IL-4/IL-13 in AD [4], and TNF-α/IL-23/IL17 in PS [5,6], both conditions remain uncured, and their frequent relapse episodes deteriorate the quality of life of the patients. Activation of AHR upregulates the expression of barrier-related proteins and accelerates terminal keratinocyte differentiation [15,16,17]. We summarize the diverse roles of exogenous and endogenous AHR ligands in skin homeostasis, as well as in the treatment of AD and PS (Table 1)
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