title: The Wnt/β-catenin pathway attenuates experimental allergic airway disease.
abstract: 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.
authors.affiliation: Pulmonary Department, III. Medical Clinic, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany; C.Taube@lumc.nl sebastian.reuter@unimedizin-mainz.de.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Reuter
authors.affiliation: Pulmonary Department, III. Medical Clinic, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany;
authors.forename: Helen
authors.initials: H
authors.lastname: Martin
authors.affiliation: Pulmonary Department, III. Medical Clinic, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany;
authors.forename: Hendrik
authors.initials: H
authors.lastname: Beckert
authors.affiliation: Department of Dermatology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany;
authors.forename: Matthias
authors.initials: M
authors.lastname: Bros
authors.affiliation: Department of Dermatology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany;
authors.forename: Evelyn
authors.initials: E
authors.lastname: Montermann
authors.affiliation: Pulmonary Department, III. Medical Clinic, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany;
authors.forename: Christina
authors.initials: C
authors.lastname: Belz
authors.affiliation: Pulmonary Department, III. Medical Clinic, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany;
authors.forename: Anke
authors.initials: A
authors.lastname: Heinz
authors.affiliation: Transgenic Facility, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany;
authors.forename: Svetlana
authors.initials: S
authors.lastname: Ohngemach
authors.affiliation: III. Medical Clinic, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany;
authors.forename: Ugur
authors.initials: U
authors.lastname: Sahin
authors.affiliation: Institute of Immunology, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Stassen
authors.affiliation: Pulmonary Department, III. Medical Clinic, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany;
authors.forename: Roland
authors.initials: R
authors.lastname: Buhl
authors.affiliation: Transgenic Facility, University Medical Center, Johannes Gutenberg University Mainz, 55131 Mainz, Germany;
authors.forename: Leonid
authors.initials: L
authors.lastname: Eshkind
authors.affiliation: Department of Pulmonology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands C.Taube@lumc.nl sebastian.reuter@unimedizin-mainz.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Taube
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D005434:Flow Cytometry; D018021:Lithium Chloride / Q000276:immunology / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D051155:Wnt1 Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051176:beta Catenin / Q000276:immunology* / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D051155:Wnt1 Protein; D051176:beta Catenin; D010047:Ovalbumin; D018021:Lithium Chloride; D004318:Doxycycline