Reuter Sebastian, Martin Helen, Beckert Hendrik, Bros Matthias, Montermann Evelyn, Belz Christina, Heinz Anke, Ohngemach Svetlana, Sahin Ugur, Stassen Michael, Buhl Roland, Eshkind Leonid, Taube Christian
Pulmonary Department, III. Medical Clinic, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany;
Department of Dermatology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany;
J Immunol. 2014 Jul 15;193(2):485-95. doi: 10.4049/jimmunol.1400013. Epub 2014 Jun 13.
Signaling via the Wnt/β-catenin pathway plays crucial roles in embryogenesis and homeostasis of adult tissues. In the lung, the canonical Wnt/β-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 × 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 β-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 β-catenin degradation. These results demonstrate an important role for the canonical Wnt/β-catenin pathway in the DC-mediated regulation of allergic responses in the lung.
通过Wnt/β-连环蛋白信号通路在胚胎发育和成人组织稳态中发挥关键作用。在肺中，经典的Wnt/β-连环蛋白信号通路与重塑过程、肺气肿的发展以及纤维化有关。然而，其在调节肺部过敏反应中的相关性仍不清楚。使用具有肺特异性诱导型（强力霉素）Wnt-1表达的基因改造小鼠（CCSP-rtTA×tetO-Wnt1），分析了Wnt对过敏性气道疾病发展的影响。在过敏原激发阶段过表达Wnt可减轻急性模型以及二次激发的更具治疗性模型中的气道炎症发展。在激发过程中用LiCl处理过敏原致敏小鼠进一步支持了这些发现。与Wnt类似，LiCl可防止β-连环蛋白降解，从而减轻过敏性气道炎症和高反应性。迁移研究表明，Wnt在肺中的特异性表达减少了过敏原激发后负载抗原的树突状细胞（DC）向引流淋巴结的迁移。给予体外负载过敏原的DC可克服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细胞活化。这些结果表明经典的Wnt/β-连环蛋白信号通路在DC介导的肺部过敏反应调节中起重要作用。
