A pro-inflammatory role for the Frizzled-8 receptor in chronic bronchitis

Anita I. R. Spanjer*, Mark H. Menzen, Akkelies E. Dijkstra, Maarten van den Berge, H. Marike Boezen, David C. Nickle, Don D. Sin, Yohan Bosse, Corry-Anke Brandsma, Wim Timens, Dirkje S. Postma, Herman Meurs, Irene H. Heijink, Reinoud Gosens

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)312-322
Number of pages11
JournalThorax
Volume71
Issue number4
DOIs
Publication statusPublished - Apr-2016

Keywords

  • OBSTRUCTIVE PULMONARY-DISEASE
  • EXTRACELLULAR-MATRIX PRODUCTION
  • AIRWAY SMOOTH-MUSCLE
  • GENE-EXPRESSION
  • CIGARETTE-SMOKE
  • MOLECULAR-MECHANISMS
  • EPITHELIAL-CELLS
  • COPD
  • FIBROBLASTS
  • SECRETION

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