O08 The aryl hydrocarbon receptor pathway is differentially regulated in psoriasis and atopic dermatitis with implications for therapeutic intervention

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor with anti-inflammatory and barrier functions in skin. Activated AHR induces expression of CYP1A1, which metabolizes AHR ligands providing a negative feedback mechanism controlling AHR activation. We and others have shown a dysregulation of the AHR pathway in psoriasis and atopic dermatitis (AD), but the underlying causes are ill understood. With AHR now a therapeutic target for both conditions, we sought to investigate the AHR pathway to elucidate the mechanisms preventing its anti-inflammatory function in psoriasis and AD. Skin biopsies were taken from patients with AD (n = 17) and psoriasis (n = 22) not receiving systemic treatment and healthy volunteers matched for age, sex and site (n = 31). The biopsies were used to assess (i) AHR and CYP1A1 expression in skin by quantitative reverse-­transcriptase polymerase chain reaction and (ii) CYP1 enzymatic activity in epidermal sheets by EROD (7-ethoxyresorufin O-deethylase) assay. AHR is significantly increased in lesional AD (n = 7, P < 0.05) vs. healthy skin (n = 9), while CYP1A1 shows a downward trend in lesional AD vs. healthy controls. CYP1 enzymatic activity shows no difference (P > 0.05) in basal or inducible activity in lesional AD (n = 10) vs. healthy epidermis (n = 10). In psoriasis, AHR is significantly decreased in lesional skin (n = 18, P < 0.01) vs. healthy skin (n = 9), while CYP1A1 is marginally reduced (P = 0.055). Healthy and psoriasis epidermis cultured with an AHR ligand upregulates CYP1A1 expression in all tissues (n = 7, q < 0.05). However, the induced CYP1 enzymatic activity is inhibited in lesional psoriasis skin (n = 8, q > 0.05) vs. healthy and psoriasis nonlesional epidermis (n = 8, q < 0.05). This inhibition is driven by tumour necrosis factor (TNF), shown by a reduction of CYP1 activity in healthy epidermis cultured with TNF (10 ng mL−1; n = 4, P < 0.01), and an upward trend in CYP1 activity in lesional psoriasis epidermis treated with adalimumab (10 μg mL−1, n = 4). Taking the results together, the AHR pathway is differentially dysregulated in AD and psoriasis, with implications for therapeutic targeting of the AHR pathway, as AHR-targeting treatments may result in different levels of response in these conditions.