TSLP Produced by Keratinocytes Promotes Allergen Sensitization through Skin and Thereby Triggers Atopic March in Mice

Abstract

Atopic dermatitis often precedes the development of asthma, a phenomenon known as "atopic march". An important role of allergen sensitization developed through barrier-defective skin has been recognized in the onset of atopic march; however, the underlying mechanism remains poorly understood. In this study, we use an experimental atopic march mouse model, in which the sensitization to allergen is achieved through barrier-impaired skin, followed by allergen challenge in the airway. By using thymic stromal lymphopoietin (TSLP)(iep-/-) mice in which the cytokine TSLP is selectively and inducibly ablated in epidermal keratinocytes, we demonstrate that keratinocytic TSLP, the expression of which is induced by skin barrier impairment, is essential for generating skin allergic inflammation and allergen-induced T helper type 2 response, for developing sensitization to allergen, and for triggering a subsequent allergic asthma. Furthermore, using TSLP(over) mice in which overexpression of keratinocytic TSLP is induced by skin topical application of MC903 (a vitamin D3 analog) in a dose-dependent manner, we show that keratinocytic TSLP levels are correlated with skin sensitization strength and asthma severity. Taken together, our study uncovers a crucial role of keratinocytic TSLP in the "atopic march" by promoting allergen sensitization occurring in barrier-impaired skin, which ultimately leads to allergic asthma.