Inflammatory skin diseases like psoriasis and atopic dermatitis (AD) pose significant challenges due to their chronic nature and impact on quality of life. Traditional treatments often have limitations, spurring the investigation of novel therapeutic targets. The aryl hydrocarbon receptor (AHR) has emerged as a critical regulator of skin homeostasis, with its activation by endogenous ligands resulting in beneficial effects, such as maintaining skin barrier integrity and constraining inflammation. The clinical approval of tapinarof, a topical AHR modulating drug, for psoriasis and its potential use in AD, highlights the therapeutic potential of targeting the AHR pathway to harness its beneficial effects in skin inflammation.
Key Points
•AHR Pathway and Activation:
◦AHR is a ligand-activated transcription factor that regulates gene expression via the Xenobiotic Response Element (XRE).
◦Activation of AHR induces the expression of genes involved in regulating its activity, providing negative feedback mechanisms.
◦AHR can be activated by both exogenous toxins and physiological ligands, with the latter undergoing biotransformation into nontoxic metabolites.
•AHR Ligands:
◦Exogenous ligands include polyhalogenated aromatic hydrocarbons (HAHs) and polycyclic aromatic hydrocarbons (PAHs).
◦Physiological ligands include tryptophan metabolites, such as 6-formylindolo[3,2-b] carbazole (FICZ), and dietary compounds like indole-3-carbinol (I3C).
◦Manuka honey and tapinarof can also activate the AHR pathway.
•AHR Expression and Function in Healthy Skin:
◦AHR is expressed in keratinocytes, melanocytes, fibroblasts, and immune cells in the skin.
◦AHR promotes keratinocyte differentiation, skin barrier formation, and the production of IL-22, which is involved in keratinocyte proliferation and differentiation.
◦AHR also influences the function of immune cells, such as Th17 cells, ILCs, and DCs.
•AHR in Psoriasis:
◦Lack of AHR signaling can exacerbate psoriasiform inflammation.
◦Tapinarof has shown promise in preclinical and clinical studies for treating psoriasis.
◦There are conflicting reports regarding AHR and CYP1A1 expression in psoriasis lesional versus healthy skin, suggesting inter-individual variability.
•AHR in Atopic Dermatitis:
◦Physiological AHR activation restores the compromised skin barrier and reduces inflammation in AD.
◦Tapinarof is being investigated as a therapy for AD, with promising results from phase 3 trials.
◦AHR transcript and protein expression is consistently increased in AD lesional skin; however, reports on CYP1A1 expression are conflicting.
This review highlights the AHR pathway as a promising therapeutic target for inflammatory skin diseases. The approval of tapinarof marks a significant advancement, but discrepancies in AHR expression and activation in psoriasis and AD warrant further investigation. Future research should focus on identifying additional checkpoints within the AHR pathway that are amenable for therapeutic intervention in skin inflammation. Studies of other inflammatory skin conditions like contact dermatitis, acne, and frontal fibrosing alopecia (FFA) may also benefit from AHR modulation as a possible therapeutic strategy.
Link to the study: https://www.mdpi.com/1422-0067/26/4/1618
