Unravelling the role of AHR signaling in microbe-host interaction in the skin

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Recent findings indicate that human health is ‘multiorganismal’. Interactions between commensal or pathogenic microbes and the hosts they colonize are central to the maintenance of homeostasis and the initiation of disease. Detailed knowledge on the skin microbiome and its alterations in a variety of skin diseases is now available. However, specific interactions between microbes and skin cells of the host, including avenues of inter-organismal cell-to-cell communication are less well understood. Recently, it became apparent that a well-known communication receptor, namely the aryl hydrocarbon receptor (AHR) plays a critical role in microbe-host interactions within the gut. The AHR acts as a key sensor of metabolites produced and released by the intestinal microbiota, where they are implicated in the regulation of the mucosal immune system and intestinal barrier function. In particular, the AHR is involved in the binding of microbial-derived metabolites of the essential amino acid L-tryptophan (L-Trp). Although various members of the gut microbiome have now been shown to be involved in pathways that yield biologically active derivatives of L-Trp activating the AHR, the situation in the skin remains largely elusive. In project 1, we aim to generate evidence supporting the role for AHR signaling as a key player in microbe-host interactions maintaining cutaneous homeostasis and when perturbed, facilitating chronic skin inflammation. We are investigating healthy skin and distinct chronic inflammatory skin diseases, such as atopic dermatitis and psoriasis, which have been shown to depend on AHR signaling. The applicant will mine datasets from the unique physical biomaterial collection of project 1 and combine these with recently available public datasets (incl. single cell RNA-Seq data) as well as newly generated transcriptome and microbiome analyses. Here, the applicant will build on these multi-omics datasets to investigate the following specific aims: (1) Unravel the microbe-driven dynamics of Trp-catabolism-dependent cutaneous AHR signaling during homeostasis and chronic skin inflammation. (2) Define functional consequences in keratinocytes, sensory neurons and Schwann cells as cellular targets for AHR ligands to mediate microbe-host interactions in vitro. (3) Validate the modulation of cutaneous homeostasis and chronic skin inflammation through microbe-induced AHR signaling in mice and man in vivo. Findings of the proposed study may shed light into the role of AHR signaling in the interaction pathways between microbes and the host. It may identify important ‘beneficial’ vs. ‘harmful’ microbes as well as their products and define novel strategies based on AHR targeting, which help to maintain cutaneous homeostasis and therapeutically modulate skin inflammation.