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

MD Anderson Cancer Center, United States of America
PLoS Biology (Impact Factor: 9.34). 06/2009; 7(5):e1000067. DOI: 10.1371/journal.pbio.1000067
Source: PubMed


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-TSLP(tg) 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.

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Available from: Mitsuru Morimoto, Aug 18, 2014
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    • "Zhu et al.87 used IL-13 transgenic mice treated with OVA. Demehri et al.88 used RBP-jCKO mice treated with OVA, and Hershko et al.89 used Ox challenge with OVA treatment. Although all of these models expressed AD-like skin lesions combined with asthma-like lung lesions, the methods relied on intraperitoneal injections of OVA for sensitization, not epicutaneous sensitization via damaged skin barriers. "
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    • "Using Nippstrongylus brasiliensis as a model for inducing acute lung damage Chen et al. (2012) demonstrated that Th2 cytokines IL-4 and IL-13 were important in controlling IL-17-induced inflammation and lung damage while insulin-like growth factor 1 (IGF-1) and IL-10 stimulated the development of alternatively activated M2 macrophages which played a central role in wound healing. Amongst the earliest signals of damage which influences the development of wound healing responses is thymic stromal lymphopoietin (TSLP), a cytokine that is up-regulated by damage or trauma to epithelial cells (Allakhverdi et al., 2007; Demehri et al., 2009). Several studies have proposed that TSLP is both necessary and sufficient for the initiation of Th2-based inflammation (Soumelis et al., 2002; Yoo et al., 2005; Zhou et al., 2005; Omori and Ziegler, 2007). "
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    • "Especially, some keratin proteins have been documented in the study of the pathological process of pterygium lately, and were predominantly defined in the epithelium layer [8,9]. As a type I keratin, keratin 17 (K17) is associated with several skin diseases [10,11] and is present in various carcinomas [12]. Overexpression of K17 is correlated with a poor prognosis in breast [13,14] and pancreatic cancers [15]. "
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