Skin-Derived TSLP Triggers Progression from Epidermal-Barrier Defects to Asthma

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Abstract
Asthma is a common allergic lung disease frequently affecting individuals with a prior history of eczema/atopic dermatitis (AD); however, the mechanism underlying the progression from AD to asthma (the so-called “atopic march”) is unclear. Here we show that, like humans with AD, mice with skin-barrier defects develop AD-like skin inflammation and are susceptible to allergic asthma. Furthermore, we show that thymic stromal lymphopoietin (TSLP), overexpressed by skin keratinocytes, is the systemic driver of this bronchial hyper-responsiveness. As an AD-like model, we used mice with keratinocyte-specific deletion of RBP-j that sustained high systemic levels of TSLP. Antigen-induced allergic challenge to the lung airways of RBP-j–deficient animals resulted in a severe asthmatic phenotype not seen in similarly treated wild-type littermates. Elimination of TSLP signaling in these animals blocked the atopic march, demonstrating that high serum TSLP levels were required to sensitize the lung to allergic inflammation. Furthermore, we analyzed outbred K14-TSLPtg mice that maintained high systemic levels of TSLP without developing any skin pathology. Importantly, epidermal-derived TSLP was sufficient to trigger the atopic march, sensitizing the lung airways to inhaled allergens in the absence of epicutaneous sensitization. Based on these findings, we propose that in addition to early treatment of the primary skin-barrier defects, selective inhibition of systemic TSLP may be the key to blocking the development of asthma in AD patients. Eczema (atopic dermatitis) is a common allergic skin inflammation that has a particularly high prevalence among children. Importantly, a large proportion of people suffering from eczema go on to develop asthma later in life. Although the susceptibility of eczema patients to asthma is well documented, the mechanism that mediates “atopic march”—the progression from eczema to asthma—is unclear. We used genetic engineering to generate mice with chronic skin-barrier defects and a subsequent eczema-like disorder. With these mice, we were able to investigate how skin-specific defects predisposed the lungs to allergic asthma. We identified thymic stromal lymphopoietin (TSLP), a cytokine that is secreted by barrier-defective skin into the systemic circulation, as the agent sensitizing the lung to allergens. We demonstrated that high systemic levels of skin-derived TSLP were both required and sufficient to render lung airways hypersensitive to allergens. Thus, these data suggest that early treatment of skin-barrier defects to prevent TSLP overexpression, and systemic inhibition of TSLP, may be crucial in preventing the progression from eczema to asthma.