FOR 5489:  Understanding aryl hydrocarbon receptor (AHR) signalling in skin disorders

• Subject Area: Medicine
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 495676076

The aryl hydrocarbon receptor (AHR), a highly prevalent transcription factor in skin cells, binds to and is triggered by small chemicals, including UV-generated amino acid derivatives, plant-derived dietary compounds, microbial metabolites, environmental pollutants, as well as recently developed drugs and cosmetic actives. Overall, AHR has been identified as an important link integrating such environmental, physiological and therapeutical cues for the skin. However, there is still sparse knowledge why the outcome can be beneficial or adverse for human health. The level of complexity is well illustrated by atopic eczema: A chronic activation of AHR by environmental pollutants may trigger the development and aggravation of atopic eczema, and thus, inhibition of AHR activation should be beneficial. This is, however, in contrast to the clinical observation that chronically inflamed atopic eczema can be treated successfully by topical application of AHR agonists found in coal tar and thus by stimulating AHR activation. Our research group hypothesizes that the result of AHR activation for human health (good or bad for skin) depends on the context, and that this dependency in healthy vs. inflamed skin vs. xenobiotically stressed skin results from differences in the respective microenvironment. In this regard, decisive factors most likely include the activation and differentiation state of skin resident and skin-infiltrating cell populations, integrity of the skin barrier, the skin and gut microbiome, and still to be defined influencing factors. In order to test this concept, we propose a research programme which is interdisciplinary in nature and combines expertise in basic and clinical dermatological research, immunodermatology, and dermatotoxicology. Using a range of (environmentally, life-style, therapeutically-) relevant AHR ligands, and capitalizing on our previously assembled unique AHR tools and clinical data, we will study AHR activation and inhibition mechanisms and outcome in the two inflammatory skin diseases atopic dermatitis and autoimmune Lupus erythematosus, as well as in melanoma and non-melanoma skin cancer. The nine projects will assess the role of AHR signalling as a master regulator in such skin diseases with a special focus on skin / gut microbe-host interactions, crosstalk with retinoic acids and selected pharmaceuticals, AHR´s impact on malignant transformation, as well as the relevance of the AHR repressor. We expect that this unique approach will allow us to better understand the precise role of AHR signalling in a specific clinical context and that this information can be translated into innovative preventive and therapeutic strategies.

• DFG Programme: Research Units

Projects

• AHR as a master regulator in cutaneous and systemic autoimmunity (Applicant Loser, Karin )
• AHR-mediated mechanisms to overcome vascular barriers in autoimmunity (Applicant Meuth, Sven G. )
• Cell type-specific regulation and function of the AHRR in skin inflammation and allergy (Applicant Weighardt, Heike )
• Coordination Funds (Applicant Krutmann, Jean )
• Crosstalk between AHR signaling and retinoids in skin (Applicant Krutmann, Jean )
• From actinic keratosis to invasive squamous cell carcinoma: Impact of AHR and p27KIP1 on malignant transformation (Applicant Haarmann-Stemmann, Thomas )
• Role of the AHR in cutaneous adverse drug reactions (Applicant Meller, Stephan )
• Role of the AHR pathway in UV-induced initiation and progression of melanoma and in resistance to therapy (Applicant Tüting, Thomas )
• The role of AHR for the gut-skin inflammatory axis (Applicant Esser, Charlotte )
• Unravelling the role of AHR signaling in microbe-host interaction in the skin (Applicant Homey, Bernhard )

• Spokesperson: Professor Dr. Jean Krutmann