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A pro-inflammatory role for the Frizzled-8 receptor in chronic bronchitis
  1. Anita I R Spanjer1,2,
  2. Mark H Menzen1,2,
  3. Akkelies E Dijkstra2,3,
  4. Maarten van den Berge2,3,
  5. H Marike Boezen2,4,
  6. David C Nickle5,
  7. Don D Sin6,7,
  8. Yohan Bossé8,9,
  9. Corry-Anke Brandsma2,10,
  10. Wim Timens2,10,
  11. Dirkje S Postma2,3,
  12. Herman Meurs1,2,
  13. Irene H Heijink2,3,10,
  14. Reinoud Gosens1,2
  1. 1Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands
  2. 2Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  3. 3Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  4. 4Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  5. 5Departments of Genetics and Pharmacogenomics, Merck Research Laboratories, Boston, Massachusetts, USA
  6. 6Center for Heart Lung Innovation, The University of British Columbia, Vancouver, British Columbia, Canada
  7. 7Respiratory Division, University of British Columbia, Vancouver, British Columbia, Canada
  8. 8Institut universitaire de cardiologie et de pneumologie de Québec, Québec City, Canada
  9. 9Department of Molecular Medicine, Laval University, Québec City, Canada
  10. 10Department of Pathology & Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  1. Correspondence to Anita I R Spanjer, Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, Groningen 9713 AV, The Netherlands; a.i.r.spanjer{at}rug.nl

Abstract

Rationale 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.

  • COPD ÀÜ Mechanisms
  • COPD Pharmacology
  • COPD Pathology
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