Project Details
Projekt
Cell type-specific regulation and function of the AHRR in skin inflammation and allergy
Applicant
Privatdozentin Dr. Heike Weighardt
Subject Area
Dermatology
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 495676076
AHR signalling is controlled via several mechanisms to ensure proper regulation of xenobiotic metabolism and immune processes. Enzymes of the cytochrome P450 (CYP) family, namely CYP1A1, CYP1B1 and CYP1A2 and the AHR repressor (AHRR) are AHR target genes and also important feedback control mechanisms of AHR activation. To analyse the function of AHRR in vivo, we generated AHRR-reporter mice and found that AHRR expression is intense in immune cells of barrier organs, such as gut and skin, and less pronounced in epithelial cells. AHR-dependent CYP1 family members, however, might be more active in epithelial cells. Therefore, we hypothesize, that AHR signalling might be regulated differentially in distinct cell types and this might be crucial for understanding AHR function in skin. Given the importance of the crosstalk of epithelial and immune cells at barrier organs, we want to explore the function of the AHRR and the AHR-dependent CYP1 enzymes in skin inflammation and allergy. We will compare the immunopathology and disease severity of AHRR-deficient mice, mice deficient for the AHR-dependent CYP1 enzymes and mice deficient for both, CYP1 enzymes and AHRR in mouse models of contact hypersensitivity and atopic dermatitis like skin inflammation. Further, we want to address the question how AHRR and CYP1 expression are regulated on transcriptional and epigenetic levels in skin epithelial cells versus immune cells and why AHRR expression in immune cells but to a lesser degree in keratinocytes is important for AHR activation during skin homeostasis, inflammation and allergy. With this global approach we also want to identify novel differentially regulated target genes in these cell types which might contribute to AHR regulation on a single cell level. To test a putative detrimental role of forced AHRR expression in epithelial cells we will generate mice to cell type-specifically express AHRR in vivo and analyze the impact of forced AHRR expression in keratinocytes for skin homeostasis, barrier function and allergy. In summary, in this project we intend to elucidate the molecular basis for the different regulation mechanism in immune cells versus keratinocytes to broaden and intensify the knowledge of regulatory networks of AHR function in skin.
DFG Programme
Research Units
