The skin is a barrier tissue with a large surface area in contact with the external environment and its own microbial flora. As such, immune responses in the skin must be tightly regulated to avoid unwanted and potentially harmful responses to innocuous environmental substances and commensal antigens, while allowing responses to a wide array of cutaneous pathogens. The consequences of dysregulated immune responses in the skin can be dire and include inflammatory diseases such as psoriasis, scleroderma and pemphigus vulgaris, as well as allergic responses that lead to acute and chronic atopic dermatitis (AD) and allergic contact dermatitis (ACD). We have shown that transgenic overexpression of the cytokine thymic stromal lymphopoietin (TSLP) specifically in the skin results in severe cutaneous inflammation resembling chronic AD. This inflammation is characterized by hyperactivation of CD4+ T cells and development of a strongly biased Th2 response, elevated serum levels of IgE, and severe dermal infiltration T cells, mast cells and eosinophils. Surprisingly, TSLP-overexpressing mice lacking T cells still develop the characteristic cutaneous inflammation, suggesting that myeloid cells are sufficient for the induction of TSLP-induced inflammation in the skin. The central hypotheses driving the experiments proposed in this study are that regulated expression of TSLP by keratinocytes activates resident myeloid cells in the skin, resulting in the induction of a cutaneous Th2 response and allergic inflammation in the skin. Strongly dysregulated TSLP expression in the skin causes myeloid cell hyperactivation, resulting in severe cutaneous immunopathology and development of strong Th2- mediated inflammation. To test these hypotheses and further define the role of TSLP in driving allergic inflammation, we will 1) Define the molecular pathways that lead to TSLP expression in the skin, 2) Determine the role of resident skin myeloid cells in initiating TSLP-mediated skin inflammation, and 3) Define the mechanisms by which TSLP controls dendritic cell migration during induction of TH2 responses in vivo.
Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are common inflammatory disease of the skin that are characterized by intense pruritus and chronic eczematous plaques that are often associated with a personal or family history of atopy. The etiology and pathogenesis of these diseases remain poorly characterized. The proposed experiments will help define the role of a novel cytokine, TSLP, in the induction and progression of AD and ACD. This in turn will help guide efforts to develop new interventions for these and other skin inflammatory diseases that directly or indirectly target TSLP.
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