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

人类皮肤经常暴露于微生物，包括潜在的病原体以及肠道微生物群的成员。为了控制微生物的生长，角质形成细胞产生防御分子，如抗菌肽（AMP）和细胞因子。为了产生这种防御分子，微生物必须被模式识别受体（PRR）感知。微生物的细胞内传感可以通过炎性体介导，炎性体是一种催化细胞因子如IL-1 β分泌的多蛋白复合物。我们可以证明，皮肤相关致病菌葡萄球菌（S.）金黄色葡萄球菌诱导角质形成细胞中炎性小体依赖性IL-1 β的产生。相反，在用皮肤相关的细菌葡萄球菌（S.）表皮此外，我们的初步工作表明，细胞内的芳烃受体（AhR）介导的IL-1 β和AMP的角质形成细胞刺激S。aureus和S.表皮这表明AhR作为PRR在角质形成细胞中感知细菌的尚未被认识到的新作用。该项目的目的是更深入地了解导致S。aureus-和S.表皮病介导的角质形成细胞中IL-1 β和AMP的产生和释放，特别强调炎性小体和AhR的作用。在这方面，我们将评估的AhR作为一种新的PRR在角质形成细胞介导的防御分子的生产的作用。更好地理解由角质形成细胞介导的先天防御机制可能有助于开发新的治疗策略，例如通过靶向诱导防御分子如AMP。

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.