Control of skin homeostasis by keratinocytes dependent on UVB-inducible PAS family transcription factors HIF-1a and AhR

• Applicant: Dr. Sonja Fassbender
• Subject Area: Dermatology ; Immunology
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 407582316

The skin possesses mechanisms to sense the environment and to initiate adaptive processes to changing conditions. UVB irradiation is a major environmental factor inducing pro-mutagenic DNA lesions, but also the synthesis of vitamin D and serotonin. Adaptative mechanisms to repeated UVB irradiation comprise tanning and acanthosis. UVB-induced immunosuppression by acute or chronic exposure frequently ameliorates chronic inflammatory skin disease but also increases skin cancer risk. Epidermal keratinocytes as the main UVB-exposed cell type are constantly renewed from the basal layer. They interact with surrounding cell types like melanocytes, Langerhans cells and T cells. The structurally related transcription factors HIF-1a (Hypoxia-inducible factor 1a) and AhR (Aryl hydrocarbon receptor) are both responsive to UVB radiation in keratinocytes and dimerize with the co-factor ARNT, but activate different target genes resp. processes. Hence, they act as environmental sensors. While HIF-1a is important during tissue oxygen shortage, the AhR is a prominent activator of xenobiotic response metabolism. Both modulate immune responses and regulate DNA repair activity upon UVB irradiation. Their interaction is scarcely studied, especially in keratinocytes. In this project, we want to investigate, in which manner the combined function of HIF-1a and AhR in keratinocytes is relevant for the regulation of skin functions under homeostasis as well as for the induction of immune responses. For this, we bred keratinocyte-specific double-KO mice (“DcKO”) and generated human single and double-KO HaCaT keratinocytes for HIF-1a and AhR. Our previous findings show that the skin of DcKO mice exhibits several characteristics compared to WT and single-cKO animals, which would be expected in UVB-irradiated (wildtype) animals: i.a. hyperpigmentation, acanthosis and reduced Langerhans cells. This results in the question whether these animals possess pre-existing improved protection against UVB radiation or whether the findings are a consequence of constantly increased stress responses. Further we want to assess whether the cutaneous immune defense of these animals is disturbed similarly to UVB-induced immunosuppression of the wildtype. Moreover, we aim to identify underlying intracellular processes, which could be activated in a dysregulated or possibly compensatory manner. These questions will be addressed through the following approaches: single cell transcriptomics of murine skin (cell types, gene expression), in vivo experiments (comparison of immune responses to UVB radiation vs. FITC as a model allergen) and cell culture assays (signaling pathways in human HaCaT keratinocytes). We expect to gain novel insights into the complex regulation of skin functions under changing environmental conditions by sensor functions of keratinocytes.

• DFG Programme: Research Grants