Investigating the transcriptional regulation of the environmental sensor skin disease

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Describe background to the work including that carried out in the supervisor's own team and previous work. [This information will be used by the reviewers to understand the context of the proposed study]. Atopic Dermatitis (AD) is a chronic inflammatory skin disease affecting over 200 million people worldwide and severely impacting the patient's quality of life. While treatment has improved since the development of biological therapies targeting the specific immune dysregulation, not all patients will respond to these therapies, highlighting the need for more therapeutic targets. The Aryl Hydrocarbon Receptor (AHR) is an evolutionarily conserved transcription factor and environmental sensor, expressed at barrier organs, like skin, where it has a homeostatic role, maintaining skin barrier integrity and reducing inflammation (1, 2). Once bound by its ligand, AHR can translocate into the nucleus where it can bind to its partner AHR Nuclear Translocator (ARNT). The AHR/ARNT dimer can then bind to regions of DNA that possess the Dioxin Response Element (DRE), initiating the transcription of AHR's target genes or gene battery: AHRR encoding for the AHR repressor, and the xenobiotic metabolising Cytochrome P450-1 enzymes CYP1A1, CYP1A2, and CYP1B1 . AHR signalling is regulated at three levels indicating a physiological importance for monitoring the AHR pathway: the AHR repressor (AHRR) can disrupt the AHR/ARNT dimer preventing further transcription induction, proteasomal degradation of AHR , and most importantly, a negative feedback mechanism by ligand metabolism by the Cytochrome P450-1 (CYP1) family of enzymes [1] which are designed to prevent overactivation of the pathway by clearing the remaining ligands following AHR activation. AHR most potent exogenous ligand is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), responsible for dioxin poisoning cases [1]. These exogenous ligands are stable and resistant to metabolism by the CYP1 enzymes, leading to persistent signalling which, in turn, contributes to the reported liver toxicity and excessive immune suppression induced by AHR activation. In contrast, physiological ligands are rapidly metabolised by CYP1 enzymes, leading to transient signalling. They are mostly derived from tryptophan metabolites and the host microbiome , which implies a physiological function for AHR. These tryptophan metabolites include 6-formylindolo[3,2-b]carbazole (FICZ) generated by UV radiation in the skin, Indole-3-Acetic Acid and Indole-3-Propionic Acid generated from microbial metabolism, and Kynurenine (ligand precursor) and Kynurenic Acid via host enzymatic metabolism]. Research by our lab has shown a dysregulation in the AHR pathway in the inflammatory skin disease psoriasis (3), as well as in AD (unpublished data) with regards to expression of AHR and its target gene CYP1A1. Tapinarof, a topical AHR agonist, has been tested in a phase 3 clinical trial for AD (Clinical Trial Identifier NCT05032859), and has been approved to treat psoriasis (4). Tapinarof treatment reduces inflammatory mediators, increases skin barrier function, and promotes clearance of the lesions. However, AHR activation is double-edged, as it is capable of beneficial physiological functions as well as toxicity by excessive immunosuppression (1), highlighting the need for further research into the AHR/CYP1A1 axis. The importance of investigating the finer details of this axis is two-fold: 1) Safeguarding as overactivation of the axis can result in overt immunosuppression, and 2) to harness its maximum potential as a therapeutic target for inflammatory skin diseases