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

被引:172
作者
Demehri, Shadmehr [1 ,2 ]
Morimoto, Mitsuru [1 ,2 ]
Holtzman, Michael J. [3 ]
Kopan, Raphael [1 ,2 ]
机构
[1] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO 63130 USA
[2] Washington Univ, Sch Med, Div Dermatol, St Louis, MO 63110 USA
[3] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA
来源
PLOS BIOLOGY | 2009年 / 7卷 / 05期
基金
美国国家卫生研究院;
关键词
THYMIC STROMAL LYMPHOPOIETIN; ATOPIC-DERMATITIS; T-CELLS; ALLERGIC INFLAMMATION; FILAGGRIN MUTATIONS; AIRWAY DISEASE; NOTCH; MICE; DIFFERENTIATION; PERMEABILITY;
D O I
10.1371/journal.pbio.1000067
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
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页数:12
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