title: A pro-inflammatory role for the Frizzled-8 receptor in chronic bronchitis.
abstract: BACKGROUND
  We have previously shown increased expression of the Frizzled-8 receptor of the Wingless/integrase-1 (WNT) signalling pathway in COPD. Here, we investigated if the Frizzled-8 receptor has a functional role in airway inflammation associated with chronic bronchitis.
  
  
  METHODS
  Acute cigarette-smoke-induced airway inflammation was studied in wild-type and Frizzled-8-deficient mice. Genetic association studies and lung expression quantitative trait loci (eQTL) analyses for Frizzled-8 were performed to evaluate polymorphisms in FZD8 and their relationship to tissue expression in chronic bronchitis. Primary human lung fibroblasts and primary human airway epithelial cells were used for in vitro studies.
  
  
  RESULTS
  Cigarette-smoke-exposure induced airway inflammation in wild-type mice, which was prevented in Frizzled-8-deficient mice, suggesting a crucial role for Frizzled-8 in airway inflammation. Furthermore, we found a significant genetic association (p=0.009) between single nucleotide polymorphism (SNP) rs663700 in the FZD8 region and chronic mucus hypersecretion, a characteristic of chronic bronchitis, in a large cohort of smoking individuals. We found SNP rs663700 to be a cis-eQTL regulating Frizzled-8 expression in lung tissue. Functional data link mesenchymal Frizzled-8 expression to inflammation as its expression in COPD-derived lung fibroblasts was regulated by pro-inflammatory cytokines in a genotype-dependent manner. Moreover, Frizzled-8 regulates inflammatory cytokine secretion from human lung fibroblasts, which in turn promoted MUC5AC expression by differentiated human airway epithelium.
  
  
  CONCLUSIONS
  These findings indicate an important pro-inflammatory role for Frizzled-8 and suggest that its expression is related to chronic bronchitis. Furthermore, our findings indicate an unexpected role for fibroblasts in regulating airway inflammation in COPD.
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Anita I R
authors.identifier: http://orcid.org/0000-0003-2843-4137
authors.initials: AI
authors.lastname: Spanjer
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Menzen
authors.affiliation: Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Akkelies E
authors.initials: AE
authors.lastname: Dijkstra
authors.affiliation: Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: van den Berge
authors.affiliation: Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: H Marike
authors.initials: HM
authors.lastname: Boezen
authors.affiliation: Departments of Genetics and Pharmacogenomics, Merck Research Laboratories, Boston, Massachusetts, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Nickle
authors.affiliation: Center for Heart Lung Innovation, The University of British Columbia, Vancouver, British Columbia, Canada Respiratory Division, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Don D
authors.initials: DD
authors.lastname: Sin
authors.affiliation: Institut universitaire de cardiologie et de pneumologie de Québec, Québec City, Canada Department of Molecular Medicine, Laval University, Québec City, Canada.
authors.forename: Yohan
authors.initials: Y
authors.lastname: Bossé
authors.affiliation: Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Department of Pathology & Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Corry-Anke
authors.initials: CA
authors.lastname: Brandsma
authors.affiliation: Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Department of Pathology & Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Wim
authors.identifier: http://orcid.org/0000-0002-4146-6363
authors.initials: W
authors.lastname: Timens
authors.affiliation: Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Herman
authors.initials: H
authors.lastname: Meurs
authors.affiliation: Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Department of Pathology & Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Irene H
authors.initials: IH
authors.lastname: Heijink
authors.affiliation: Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Reinoud
authors.initials: R
authors.lastname: Gosens
mesh_terms: D000818:Animals; D029481:Bronchitis, Chronic / Q000235:genetics* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D051157:Frizzled Receptors / Q000235:genetics*; D005819:Genetic Markers / Q000235:genetics; D005838:Genotype; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000235:genetics; D008168:Lung / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D055271:Mucin 5AC / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D016207:Cytokines; D051157:Frizzled Receptors; D005819:Genetic Markers; C524678:MUC5AC protein, human; D055271:Mucin 5AC
keywords: COPD Pathology; COPD Pharmacology; COPD ÀÜ Mechanisms