FC19 A global investigation of the aryl hydrocarbon receptor pathway reveals multiple levels of dysregulation amenable for therapeutic targeting in psoriasis

Abstract The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor and environmental sensor with homeostatic roles in the skin. We and others have shown that physiological AHR activation ameliorates inflammation in psoriasis models, leading to the development of the first-in-class AHR-modulating drug, Tapinarof, for mild-to-moderate psoriasis. The AHR pathway is regulated at multiple levels, including through the cytochrome P450 1 (CYP1) enzymes, which degrade AHR ligands providing critical negative feedback. Here we aim to deeply investigate the AHR pathway to identify dysfunctional checkpoints for therapeutic intervention in psoriasis. We performed a multi-model investigation in the blood and skin of White moderate-to-severe psoriasis patients (n = 51), not receiving systemic therapy, and age/sex/ethnicity-matched healthy volunteers (n = 28), assessing AHR ligand and precursor availability in serum, AHR and CYP1A1 bulk and spatial mRNA and protein in blood and skin, in vitro modulation of AHR expression in normal human epidermal keratinocytes (NHEK) by psoriasis-relevant cytokines, and CYP1 enzymatic activity. Serum levels of the ligand precursor tryptophan were significantly decreased in psoriasis patients (P < 0.001; n = 19) vs. healthy (n = 19). AHR mRNA expression was significantly decreased in psoriasis blood (P < 0.01; n = 30) and psoriasis lesional (PsL; P < 0.01; n = 17) skin vs. healthy, while CYP1A1 mRNA expression did not differ in blood but showed a downward trend in PsL (P = 0.0546; n = 16). While AHR and CYP1A1 protein were mostly co-expressed in the suprabasal skin layers, AHR mRNA predominantly localized in the basal layer in PsL (n = 5) compared with a more widespread expression in healthy skin (n = 7), with a reduction in AHR positive cells in the PsL dermis (P < 0.05). TNF (P < 0.001) and IFN-γ (P < 0.0001) significantly upregulated AHR mRNA in NHEK (n = 4). In vitro culture of skin epidermal sheets with the AHR agonist FICZ significantly upregulated CYP1A1 mRNA expression in healthy (q < 0.05; n = 8) and psoriasis epidermis (q < 0.05; n = 7); however, CYP1 enzymatic activity was not increased by AHR ligation in PsL. In contrast, FICZ-induced CYP1 enzymatic activity was enhanced in Th17 cells from the same patients (P = 0.0535; n = 8). Finally, exposure of NHEK to a psoriasis inflammatory cocktail containing TNF, IL-23 and IL-17A resulted in a significant reduction in induced CYP1 enzymatic activity (n = 3, P < 0.05), suggesting a potential mechanism for the lack of ligand-induced activity in PsL. Taken together, our data show that there is a multi-level dysregulation of the AHR pathway in psoriasis and suggests a failure of multiple pathway checkpoints that could be further targeted to restore AHR’s beneficial effects on skin.