Abstract
The aryl hydrocarbon receptor (AHR) is an environmentally-regulated transcription factor with homeostatic and anti-inflammatory roles in skin. AHR activation leads to expression of the cytochrome P4501 (CYP1) enzyme family, which provides critical negative feedback by degrading AHR ligands. We have previously shown that excessive CYP1A1 activity impairs AHR anti-inflammatory activity in psoriasis-like skin inflammation in mice, while suppression of aberrant enzymatic activity restores AHR beneficial effect. Moreover, CYP1A1 activity is significantly enhanced in blood cells of psoriasis patients, suggesting that dysregulation of CYP1A1 activity may play a role in psoriasis. Here, we performed a multi-modal investigation of the AHR/CYP1A1 axis in the blood and skin of psoriasis patients and healthy controls, assessing availability of AHR ligands and precursors by mass spectrometry, AHR and CYP1A1 mRNA by qPCR, and CYP1A1 enzymatic activity by EROD assay. Levels of the ligand precursor tryptophan were significantly (p≤0.001) decreased in the serum of psoriasis patients (n=20) versus healthy (n=20). Expression of AHR mRNA was significantly (p≤0.001) decreased in both psoriasis blood and psoriasis lesional (PsL) skin, while CYP1A1 mRNA did not differ in blood but was significantly (p≤0.05) decreased in PsL skin. In vitro culture of skin epidermal sheets with an AHR agonist significantly (p≤0.05) upregulated CYP1A1 mRNA in healthy and psoriasis skin, but, surprisingly, CYP1A enzymatic activity was not increased by AHR ligation in PsL. We are currently studying AHR and CYP1A1 protein expression in the skin at single-cell level by imaging mass cytometry to gain further insights into the complex regulation of the pathway. Taken together, our data show that there is a multi-level dysregulation of the AHR/CYP1A1 axis in psoriasis and suggest a failure of multiple pathway checkpoints that could be targeted to restore AHR beneficial effects in skin inflammation.
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