title: Wnt Signaling in Chronic Rhinosinusitis with Nasal Polyps.
abstract: The signaling pathways that sustain the disease process of chronic rhinosinusitis with nasal polyps (CRSwNP) remain poorly understood. We sought to determine the expression levels of Wnt signaling genes in CRSwNP and to study the role of the Wnt pathway in inflammation and epithelial remodeling in the nasal mucosa. Microarrays and real time-quantitative polymerase chain reaction comparing gene expression in matched NPs and inferior turbinates revealed that WNT2B, WNT3A, WNT4, WNT7A, WNT7B, and FZD2 were up-regulated and that FZD1, LRP5, LRP6, and WIF1 were down-regulated in NPs. Immunolabeling showed robust expression of Wnt ligands, nuclear β-catenin, and Axin-2 in NP tissue, suggesting that Wnt/β-catenin signaling is activated in NPs. We used primary human nasal epithelial cell (HNEpC) cultures to test the functional consequences of Wnt pathway activation. Monolayer HNEpCs treated with recombinant human WNT (rhWNT) 3A, but not with rhWNT4, had altered epithelial morphology and decreased adhesion, without loss of viability. We found that neither rhWNT3A nor rhWNT4 treatment induced proliferation. The expression and release of inflammatory cytokines IL-6 and granulocyte-macrophage colony-stimulating factor were increased after rhWNT3A exposure of HNEpCs. When differentiated at an air-liquid interface, rhWNT3A- and WNT agonist-, but not rhWNT4-treated HNEpCs, had abnormal epithelial architecture, failed to undergo motile ciliogenesis, and had defective noncanonical Wnt (planar cell polarity) signaling. On the basis of these results, we propose a model in which Wnt/β-catenin signaling sustains mucosal inflammation and leads to a spectrum of changes consistent with those seen during epithelial remodeling in NPs.
authors.affiliation: 1 Department of Otolaryngology, Head and Neck Surgery, University of Lübeck, Lübeck, Germany.|2 Department of Otolaryngology, Head and Neck Surgery, and.
authors.forename: Robert
authors.identifier: 0000-0003-1422-5158
authors.initials: R
authors.lastname: Böscke
authors.affiliation: 3 Department of Pathology, Stanford University School of Medicine, Stanford, California; and.
authors.forename: Eszter K
authors.initials: EK
authors.lastname: Vladar
authors.affiliation: 1 Department of Otolaryngology, Head and Neck Surgery, University of Lübeck, Lübeck, Germany.
authors.forename: Michael
authors.identifier: 0000-0001-8525-4939
authors.initials: M
authors.lastname: Könnecke
authors.affiliation: 1 Department of Otolaryngology, Head and Neck Surgery, University of Lübeck, Lübeck, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Hüsing
authors.affiliation: 1 Department of Otolaryngology, Head and Neck Surgery, University of Lübeck, Lübeck, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Linke
authors.affiliation: 1 Department of Otolaryngology, Head and Neck Surgery, University of Lübeck, Lübeck, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Pries
authors.affiliation: 4 Division of Microbial Interface Biology, Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Reiling
authors.affiliation: 3 Department of Pathology, Stanford University School of Medicine, Stanford, California; and.
authors.forename: Jeffrey D
authors.identifier: 0000-0001-6094-7392
authors.initials: JD
authors.lastname: Axelrod
authors.affiliation: 2 Department of Otolaryngology, Head and Neck Surgery, and.
authors.forename: Jayakar V
authors.initials: JV
authors.lastname: Nayak
authors.affiliation: 1 Department of Otolaryngology, Head and Neck Surgery, University of Lübeck, Lübeck, Germany.
authors.forename: Barbara
authors.identifier: 0000-0002-3062-459X
authors.initials: B
authors.lastname: Wollenberg
mesh_terms: D002908:Chronic Disease; D002923:Cilia / Q000187:drug effects / Q000378:metabolism; D003199:Computer Systems; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D009298:Nasal Polyps / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D012220:Rhinitis / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D012852:Sinusitis / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D014420:Turbinates / Q000473:pathology; D051153:Wnt Proteins / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D051153:Wnt Proteins; D051176:beta Catenin
keywords: Wnt; chronic rhinosinusitis with nasal polyps; epithelial remodeling; planar cell polarity; respiratory cilia