The Wnt/β-Catenin Pathway Attenuates Experimental Allergic Airway Disease
The Wnt/β-Catenin Pathway Attenuates Experimental Allergic Airway Disease
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DOI：
10.4049/jimmunol.1400013
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发表时间：
2014-07-15
影响因子：
4.4
通讯作者：
Taube, Christian
中科院分区：
文献类型：
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作者：
Reuter, Sebastian;Martin, Helen;Taube, Christian
通过 Wnt/β-连环蛋白途径的信号传导在胚胎发生和成体组织的稳态中发挥着至关重要的作用。在肺部，经典的 Wnt/β-连环蛋白通路与重塑过程、肺气肿的发展和纤维化有关。然而，其与肺部过敏反应调节的相关性仍不清楚。使用具有肺特异性诱导型（多西环素）Wnt-1 表达（CCSP-rtTA x tetO-Wnt1）的转基因小鼠，分析了 Wnt 对过敏性气道疾病发展的影响。在过敏原攻击阶段，Wnt 的过度表达可以减轻急性模型以及更具治疗性的继发攻击模型中气道炎症的发展。在攻击过程中用氯化锂治疗过敏原致敏的小鼠进一步支持了这些发现。与 Wnt 类似，LiCl 可以防止 β-连环蛋白的降解，从而减轻过敏性气道炎症和高反应性。迁移研究表明，Wnt 的肺特异性表达减少了过敏原攻击后负载 Ag 的树突状细胞 (DC) 向引流淋巴结的迁移。体外施用负载过敏原的 DC 克服了 Wnt 介导的气道炎症抑制。此外，体外研究证实，阻断 β-连环蛋白降解会损害 DC 依赖性 T 细胞的激活。这些结果证明了经典 Wnt/β-catenin 通路在 DC 介导的肺部过敏反应调节中的重要作用。
Signaling via the Wnt/beta-catenin pathway plays crucial roles in embryogenesis and homeostasis of adult tissues. In the lung, the canonical Wnt/beta-catenin pathway has been implicated in remodeling processes, development of emphysema, and fibrosis. However, its relevance for the modulation of allergic responses in the lung remains unclear. Using genetically modified mice with lung-specific inducible (doxycycline) Wnt-1 expression (CCSP-rtTA x tetO-Wnt1), the impact of Wnt on the development of allergic airway disease was analyzed. Overexpression of Wnt during the allergen challenge phase attenuated the development of airway inflammation in an acute model, as well as in a more therapeutic model of secondary challenge. These findings were further supported by treatment of allergen-sensitized mice with LiCl during challenge. Similar to Wnt, LiCl prevented the degradation of beta-catenin and, thus, attenuated allergic airway inflammation and hyperresponsiveness. Migration studies revealed that lung-specific expression of Wnt reduced the migration of Ag-loaded dendritic cells (DCs) into the draining lymph nodes following allergen challenge. Administration of in vitro allergen-loaded DCs overcame Wnt-mediated suppression of airway inflammation. Furthermore, in vitro studies confirmed that DC-dependent T cell activation is impaired by blocking b-catenin degradation. These results demonstrate an important role for the canonical Wnt/beta-catenin pathway in the DC-mediated regulation of allergic responses in the lung.