<b><i>Staphylococcus aureus</i></b> Activates the Aryl Hydrocarbon Receptor in Human Keratinocytes

Abstract

<i>Staphylococcus aureus</i> is an important pathogen causing various infections, including – as most frequently isolated bacterium – cutaneous infections. Keratinocytes as the first barrier cells of the skin respond to <i>S. aureus</i> by the release of defense molecules such as cytokines and antimicrobial peptides. Although several pattern recognition receptors expressed in keratinocytes such as Toll-like and NOD-like receptors have been reported to detect the presence of <i>S. aureus</i>, the mechanisms underlying the interplay between <i>S. aureus</i> and keratinocytes are still emerging. Here, we report that <i>S. aureus</i> induced gene expression of CYP1A1 and CYP1B1, responsive genes of the aryl hydrocarbon receptor (AhR). AhR activation by <i>S. aureus</i> was further confirmed by AhR gene reporter assays. AhR activation was mediated by factor(s) &#x3c;2 kDa secreted by <i>S. aureus</i>. Whole transcriptome analyses and real-time PCR analyses identified IL-24, IL-6, and IL-1beta as cytokines induced in an AhR-dependent manner in <i>S. aureus</i>-treated keratinocytes. AhR inhibition in a 3D organotypic skin equivalent confirmed the crucial role of the AhR in mediating the induction of IL-24, IL-6, and IL-1beta upon stimulation with living <i>S. aureus</i>. Taken together, we further highlight the important role of the AhR in cutaneous innate defense and identified the AhR as a novel receptor mediating the sensing of the important skin pathogen <i>S. aureus</i> in keratinocytes.