FP10 Dysregulated aryl hydrocarbon receptor expression in keratinocytes and immune cells in atopic dermatitis influences its homeostatic and anti-inflammatory effects
Hannah Dawe, Isabella Tosi, Katherine Teather, Mano Nakamura, Ineta Andrijauskaite, Jonathan Barker, Catherine Smith, Paola Di MeglioAbstract
Introduction and aims
The ligand-activated transcription factor aryl hydrocarbon receptor (AhR) has anti-inflammatory and skin barrier promoting functions, which have been harnessed for the treatment of atopic dermatitis (AD) with the recent US Food and Drug Administration approval of the topical AhR ligand Tapinarof. AhR activation induces CYP1A1 expression, which metabolizes physiological AhR ligands providing a negative feedback loop. We and others have shown that the AhR pathway is dysregulated in AD, with increased AHR expression, but reduced activation, potentially caused by excessive ligand metabolism. Here, we investigate this hypothesis and further dissect AhR expression in AD.
Methods
Skin biopsies from patients with AD not receiving systemic treatment (n = 15) and age/sex-at-birth/site-matched healthy volunteers (n = 17) were used to assess: (i) spatial epidermal AhR expression by RNAscope, and (ii) CYP1 enzymatic activity in healthy and AD epidermis by ethoxyresorufin-O-deethylase assay. Publicly available single-cell RNA sequencing (scRNAseq) datasets from AD and healthy skin and blood were analysed to further investigate AHR expression.
Results
The expression pattern of AHR differs in AD vs. healthy epidermis. AHR expression is widespread throughout healthy epidermis (n = 7), whereas it localizes mostly in basal keratinocytes in AD (n = 5), which was confirmed with scRNAseq. In blood, CD1C+CLEC10A+CLEC9A+ dendritic cells, CD14+ monocytes, and CCR4+PTGDR2+IL18R1+ T helper 2 cells express the highest level of AHR, which is increased in AD vs. healthy epidermis. Finally, CYP1 enzymatic activity shows no difference (P > 0.05) in basal or inducible activity in AD (n = 10) vs. healthy epidermis (n = 10).
Conclusions
We have identified a dysregulated AHR expression within AD epidermis, with increased AHR in AD basal keratinocytes vs. healthy epidermis, and declining expression in suprabasal AD keratinocytes. CYP1 enzyme activity is normal in AD, and thus not responsible for the previously identified reduced pathway activation. Further work investigating other checkpoints of the pathway, including AhR ligand availability, will provide a full assessment of the pathway to maximize its potential as a therapeutic target in AD.