TSLP Produced by Keratinocytes Promotes Allergen Sensitization through Skin and Thereby Triggers Atopic March in Mice
TSLP Produced by Keratinocytes Promotes Allergen Sensitization through Skin and Thereby Triggers Atopic March in Mice
复制标题
DOI：
10.1038/jid.2012.239
复制
发表时间：
2013-01-01
影响因子：
6.5
通讯作者：
Li, Mei
中科院分区：
文献类型：
--
作者：
Leyva-Castillo, Juan Manuel;Hener, Pierre;Li, Mei
特应性皮炎通常先于哮喘的发展，这种现象被称为“特应性进行曲”。屏障缺陷皮肤产生的过敏原致敏作用在特应性发作的过程中发挥着重要作用；然而，其根本机制仍然知之甚少。在这项研究中，我们使用实验性特应性行军小鼠模型，其中通过屏障受损的皮肤实现对过敏原的致敏，然后在气道中进行过敏原挑战。通过使用胸腺基质淋巴细胞生成素 (TSLP)(iep-/-) 小鼠，其中细胞因子 TSLP 在表皮角质形成细胞中被选择性和诱导性消融，我们证明，由皮肤屏障损伤诱导表达的角质形成细胞 TSLP 对于产生皮肤过敏性炎症和过敏原诱导的 2 型辅助 T 反应、发展对过敏原的敏感性以及引发随后的过敏性哮喘至关重要。此外，使用 TSLPover 小鼠，其中通过皮肤局部应用 MC903（维生素 D3 类似物）以剂量依赖性方式诱导角质形成细胞 TSLP 过度表达，我们发现角质形成细胞 TSLP 水平与皮肤致敏强度和哮喘严重程度相关。总而言之，我们的研究揭示了角化细胞 TSLP 在“特应性行军”中的关键作用，通过促进屏障受损皮肤中发生的过敏原致敏，最终导致过敏性哮喘。皮肤病学研究杂志 (2013) 133, 154-163; doi：10.1038/jid.2012.239； 2012 年 7 月 26 日在线发布
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 TSLPover 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. Journal of Investigative Dermatology (2013) 133, 154-163; doi:10.1038/jid.2012.239; published online 26 July 2012