Studying biological variation in the environmental sensor and novel psoriasis drug target Aryl Hydrocarbon Receptor (AHR): expression, regulation and biomarker potential

Psoriasis is an immune-mediated, chronic inflammatory skin condition due to combination of genetic predisposition, environmental triggers, and dysregulated innate and adaptive immune responses (1). The disease has a major impact on patient’s quality of life and pose a significant financial burden on the healthcare system. Recent progress in the identification of key cellular player and molecular pathways underpinning disease pathogenesis has led to the design and use of effective targeted therapies against key pro-inflammatory cytokines. Nevertheless, not all patients respond to the current treatment, suggesting that suggesting that additional molecular pathways can be targeted for therapeutic purposes.

Most of the recent innovations have been targeted to the moderate-to-severe patient population, while patients with mild-to-moderate disease, who makes up 80% of the psoriasis population, have not benefitted from these innovations. Therefore, an unmet clinical need exists for novel, safe, effective, and affordable therapies for patients with mild-to-moderate disease.

In contrast to the substantial progress in delineating the genetic and immunological landscape of psoriasis, the study of its environmental component is largely limited to epidemiological studies. Environmental factors account for 30% of psoriasis risk but their mechanistic role in disease etiopathogenesis is ill understood. Hence, the investigation of environmentally regulated pathways may offer novel opportunities to understand disease mechanisms, identify novel therapeutic targets in psoriasis and potentially provide a scientific rationale for the implementation of lifestyle prevention measure.

The AHR is a member of the PER-ARNT-SIM (PAS) domain family of ligand-activated transcriptional regulators acting as environmental sensors to direct homeostatic changes through modulation of gene expression (2). AHR ligands include xenobiotic (e.g. dioxins) and physiological ligands, such as indole derivatives of tryptophan of dietary, light and microbial or host metabolism origin. AHR is expressed at barrier organs, such as the skin, where signals mediated by physiological ligands maintains barrier integrity and prevents excessive inflammation through direct and indirect transcriptional regulation of proinflammatory genes. Upon ligand binding, AHR translocates to the nucleus, complexes with its partner ARNT and binds the DNA on AHR Responsive Element, regulating gene expression. Target genes include cytochrome P450 (CYP) enzymes, such as CYP1A1, which provides a negative feedback metabolising AHR physiological ligands, and genes involved in keratinocytes differentiation. Earlier work by the Di Meglio Lab has put AHR under the spotlight in psoriasis, showing for the first time that AHR signalling constrains skin inflammation in psoriasis samples and disease models (3) and that that psoriasis patients display increased CYP1A1 enzymatic activity, suggesting an impairment of beneficial AHR signalling due to excessive ligand metabolism mediated by CYP1A1 (4). Importantly, topical application of tapinarof, a bacterial metabolite and AHR ligand, has shown clinical efficacy in clinical trials for psoriasis and has been approved by the FDA (5).

Thus, AHR is a critical regulator of cellular homeostasis in the skin and a desirable target for the control of skin inflammation. Currently, both the research focus and the targeting strategy mostly revolve around the ligand-mediated activation of AHR signalling. However, little is known about the transcriptional regulation of AHR in itself, and the expression profile of AHR in psoriasis remains controversial. Both the literature and our own unpublished data suggest that AHR expression and transcriptional regulation are likely to be altered in psoriasis and there may be biological variation in healthy and diseased skin of individuals from different populations. Crucially, these findings may have important clinical implications. The current therapeutic strategy harnessing the anti-inflammatory effect of the AHR pathway in skin inflammation is aimed at promoting anti-inflammatory AHR signalling by supplying AHR ligands, such as tapinarof, which however require adequate expression of AHR to be effective. Therefore, a deep understanding of AHR expression and regulation in psoriasis is a necessary step to better tailor therapeutic interventions aimed at harnessing its anti-inflammatory effect.

The purpose of this studentship is to gain better insights into the spatial expression and transcriptional regulation of AHR in the skin of psoriasis patients and healthy controls of different ethnic groups and evaluate the clinical implications of these findings in the context of tapinarof treatment optimization.

Specifics aims to be addressed are:

1)     To study the transcriptional regulation of AHR in normal and psoriasis keratinocytes

2)     To study AHR expression in psoriasis and healthy skin

3)     To investigate the ex vivo effect of the AHR ligand tapinarof and evaluate AHR expression as predictive biomarker of drug response.

The PhD student will be based at St John’s Institute of Dermatology which provides an ideal environment for psoriasis research, with an established network of immunologists, cell biologists, data analyst and academic dermatologists. The student will have access to state-of-the-art equipment and technologies to conduct this project and will be supported by mentorships schemes and training courses, tailored to their specific needs. The student will have two supervisors with complimentary expertise in immunology (Dr Di Meglio, >15 years of experience in psoriasis research and pioneering the field of AHR in psoriasis for >10 years) and clinical dermatology (Prof. Catherine Smith, > 20 years as consultant dermatologist, with profound expertise in psoriasis research and experienced PhD and MD Supervisor) and a successful collaborative history since 2013.

For information about the application process, please visit our funding webpage.

It is highly recommended to informally approach Dr. Paola Di Meglio before making an application. For administrative and application process enquiries please contact Helen Rudkin.