The gut-skin axis: bacterial stimulation in the gut shapes hapten-driven inflammation of the skin

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Abstract

Methods/Results: We addressed the functional role of gut microbiota in experimental contact hypersensitivity (CHS), a CD8 + Tc1-mediated cutaneous inflammatory model, which largely resembles allergic contact dermatitis in men. We found that germ-free mice (GF) exhibited reduced ear swelling and cellular infiltration compared to conventionally housed (Conv) mice. Importantly, re-colonized GF mice showed an unaffected CHS reaction, excluding a general defect in the GF immune system. The hapten-specific Tc1 response (T cell proliferation, IFN-γ production) did not differ in Conv and GF animals. However, lymphocytes from skin-draining lymph nodes of CHS tolerant GF mice secreted higher amounts of IL-10. Unexpectedly, ablation of the intestinal microbiota in mice, by an antibiotics-cocktail (ABX mice), completely mimicked the GF phenotype with regard to clinical symptoms, T cell response and IL-10 secretion. This indicates that gut- but not skin-associated microbiota shape immunity towards contact allergens. Moreover, a distinct set of bacteria was able to restore CHS immunity in total. Indicating that extent and quality of bacterial stimulation in the gut alter hapten-driven inflammation. Increased numbers of IL-10 producing CD25 + CD4 + T cells and restoration of CHS responses in the absence of IL-10 producing FOXP3 + Tregs or CD4 + T cells in ABX treated mice demonstrated the functional relevance of T cell-related IL-10 in CHS inhibition. As haptens can activate TLR-2 mediated processes and as these molecules are involved in cutaneous inflammation and immune tolerance, we aimed to address the CHS response in mice lacking TLR-2 under ABX and GF conditions, respectively. In the absence of TLR2-mediated signaling, the CHS was largely unaffected in GF and ABX mice, revealing that TLR2 signaling is critically involved in the control of the CHS reaction by the gut microbiome. Interestingly, GF and ABX conditions restored IL-10 secretion in TLR-2 deficient mice, demonstrating TLR2 signaling upstream of IL-10 production. Conclusions: Intestinal bacteria shape CHS inflammation via TLR2 and IL-10-mediated pathways.

Speakers from the University of Münster

Raker, Verena

Clinic for Dermatology

Publications referred to in the talk

Meeting Report: 47th Annual Meeting of the "Arbeitsgemeinschaft Dermatologische Forschung") Stary, G; Fabri, M; Gebhardt, C; Eming, R; Matthias, J; Vorobyev, A; Effern,M;, Strobl, J; Günther, C; Zielinski,C; Dudziak, C; Géraud. C; Raker, V; Butze, M; Zhao, F; Wang, Y; Gerloff, D; Bertschi, NL; Gaffal, E; Buhl, T (2021) In: Experimental Dermatology, 31(10), 1641-1651. doi:10.1111/exd.14546. Conference report (journal) | Peer reviewed | Published

Distinctions received for talk

ADF/ECARF-Award for European Allergy Research 2021 (1st prize) Awarded by: Arbeitsgemeinschaft Dermatologische Forschung (ADF) Award given to: Raker, Verena K Announced at: 20/02/2021 | Date of awarding: 20/02/2021 Type of distinction: Best presentation award