Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with skin barrier defects and microbial dysbiosis. The development and progression of AD critically depends on the action of type 2 immune cells and mediators. However, the identity of these immune cells as well as their chronological appearance in the establishment of AD are still elusive. This project aims to disclose the kinetics and cellular contributors of type 2 immune responses in AD, focusing on the dynamics of interleukin (IL)-4 induction during skin inflammation in pre-clinical models. To mimic skin barrier impairment, mice were subjected to repeated tape stripping (TS) of their shaved back skin. Medium containing Staphylococcus aureus (S. aureus) was applied to induce microbial dysbiosis. Both conditions were induced either alone or in combination at defined time points. Using IL-4 reporter mice, we found that TS as well as the combination of TS and S. aureus increased the appearance of IL-4-producing cell types such as T helper type 2 cells, basophils and natural killer T cells in the skin, accompanied by increased mRNA expression of IL-13, IL-4, CCL17 and CCL22, 6 days after treatment. Skin-draining lymph nodes mimicked the previously described dynamics of IL-4- producing cell types. Moreover, increased mRNA expression of IL-33, CXCL1 and IL-6 was detected at early time points, accompanied by downregulation of skin barrier-forming proteins within the combined treatment with TS and S. aureus. Analyses of the skin microbiome of WT mice affirm this finding by pointing to a shift within the microbial homeostasis characterized by a predominance of Staphylococci after TS. This shows that skin barrier impairment and microbial dysbiosis act synergistically to induce the increased appearance of specific IL-4-producing cell types, as well as other features of AD. In the long term, this project will clarify the role of different type 2 cytokine- producing cells in the development of AD beyond Th2 cells and develop new treatment strategies.
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