The Aryl Hydrocarbon Receptor (AHR): Peacekeeper of the Skin

In the last decade, the aryl hydrocarbon receptor (AHR) has emerged as a critical peacekeeper for the maintenance of healthy skin. The evolutionary conservation of AHR implied physiological functions for this receptor, beyond the detoxification of man-made compounds, a notion further supported by the existence of physiological AHR ligands, notably derivates of tryptophan by the host and host microbiome. The UV light-derived ligand, 6-formylindolo3,2-bcarbazole (FICZ), anticipated a role for AHR in skin, a UV light-exposed organ, where physiological AHR activation promotes a healthy skin barrier and constrains inflammation. The clinical development of tapinarof, the first topical AHR modulating drug for inflammatory skin disease, approved by the FDA for mild-to-moderate psoriasis and poised for approval in atopic dermatitis, supports the therapeutic targeting of the AHR pathway to harness its beneficial effect in skin inflammation. Here, we describe how a tightly controlled, physiological activation of the AHR pathway maintains skin homeostasis, and discuss how the pathway is dysregulated in psoriasis and atopic dermatitis, identifying areas offering opportunities for alternative therapeutic approaches, for further investigation.