Commensal Staphylococci attenuate Staphylococcus aureus Skin Colonization and Inflammation via AHR-Dependent Signaling

Jule RiebelmannNicole KienzleBirgit SauerBirgit Schittek^*

• Universitatsklinikum Tubingen Universitats-Hautklinik Tubingen, Tübingen, Germany

Staphylococcus aureus is the leading cause of bacterial skin infections in several inflammatory skin diseases, however, is rarely detected on healthy skin. Skin barrier defects, such as in atopic dermatitis (1), promote S. aureus colonization by yet unknown mechanism. In our previous work we found that in healthy skin commensal staphylococci including Staphylococcus epidermidis (2) and Staphylococcus lugdunensis (SL) protect against S. aureus skin colonization, however, the microbiome-mediated protection is lost in inflammatory skin. Here, we investigated how microbiome-derived factors contribute to skin defense under homeostatic and inflammatory conditions. We show that released factors from SE and SL reduce S. aureus skin colonization by inducing antimicrobial peptides (AMPs) and suppressing inflammatory responses in the skin. Both, factors released by SE and SL, limit S. aureus-induced immune activation in the skin by dampening inflammatory signaling, reducing reactive oxygen species, and suppressing expression of danger-associated molecular patterns (DAMPs). We show that this anti-inflammatory effect is mediated by activation of aryl hydrocarbon receptor (AHR) signaling in keratinocytes. Mechanistically, SE and SL membrane vesicles are involved in activating AHR signaling in keratinocytes via direct vesicle-cell contact as well as by bacterial tryptophan metabolites. This protective effect is lost in inflamed skin, where it instead exacerbated inflammation due to impaired AHR activity in inflamed skin. Interestingly, co-treatment of human AD-like skin equivalents with released SE factors together with an AHR ligand effectively reduces S. aureus colonization pointing out a potential novel AHR-and microbiome-based therapeutic strategy in AD.