Orai1 Calcium Signaling Regulates The Release Of The Atopic Dermatitis Cytokine Tslp

The cytokine thymic stromal lymphopoietin (TSLP) is highly expressed in human epithelial keratinocytes in atopic dermatitis, and bronchial epithelial cells in asthma. Numerous studies suggest that TSLP acts as a master switch that triggers both the initiation and maintenance of atopic dermatitis, as well as the progression from atopic dermatitis to asthma. While many of the inflammatory actions of TSLP have been described, little is known about the molecular pathways that trigger TSLP expression by epithelial cells and how this leads to itch. Here we probe the signaling mechanisms that lead to TSLP production in human epithelial cells and identify the ion channel ORAI1 as a novel regulator of TSLP secretion. Using pharmacology and siRNA-mediated knockdown, combined with electrophysiological, biochemical and imaging techniques, we show that a variety of itch-causing compounds trigger ORAI1-dependent calcium signaling in human epithelial cells and that ORAI1 is required for the resulting expression and secretion of TSLP. With a combination of cellular and behavioral experiments, we determine that TSLP directly activates sensory neurons to cause itch-evoked scratching in a TRPA1-dependent manner. Our findings demonstrate that ORAI1 is an essential regulator of the atopic dermatitis cytokine and itch-causing compound, TSLP.