The role of the aryl hydrocarbon receptor (AhR) and the inflammasome in cutaneous defense

• Applicant: Professor Dr. Jürgen Harder
• Subject Area: Dermatology
• Term: from 2009 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 158496061

Human skin is constantly exposed to microorganisms including potential pathogens as well as members of the commensal microbiota. To control microbial growth, keratinocytes produce defense molecules such as antimicrobial peptides (AMPs) and cytokines. To produce such defense molecules the microbes have to be sensed by pattern recognition receptors (PRRs). Intracellular sensing of microorganisms can be mediated via the inflammasome, a multi-protein-complex catalyzing the secretion of cytokines such as IL-1beta. We could show that the skin-relevant pathogenic bacterium Staphylococcus (S.) aureus induced inflammasome-dependent IL-1beta production in keratinocytes. In contrast, the inflammasome was dispensable for the IL-1beta production in keratinocytes treated with the skin-relevant commensal bacterium Staphylococcus (S.) epidermidis. In addition, our preliminary work suggests that the intracellular aryl hydrocarbon receptor (AhR) mediates the production of IL-1beta and AMPs in keratinocytes stimulated with S. aureus und S. epidermidis. This indicates a yet-unappreciated novel role of the AhR as PRR to sense bacteria in keratinocytes. The aim of the project is to gain more insight into the molecular mechanisms leading to the S. aureus- and S. epidermidis-mediated production and release of IL-1beta and AMPs in keratinocytes with special emphasis on the role of the inflammasome and the AhR. In this regard we will evaluate the role of the AhR as a novel PRR in keratinocytes mediating the production of defense molecules. A better understanding of the innate defense mechanisms mediated by keratinocytes may facilitate the development of novel therapeutic strategies, e.g. through the targeted induction of defense molecules such as AMPs.

• DFG Programme: Research Grants