title: Foxa3 induces goblet cell metaplasia and inhibits innate antiviral immunity.
abstract: BACKGROUND
  Goblet cell metaplasia accompanies common pulmonary disorders that are prone to recurrent viral infections. Mechanisms regulating both goblet cell metaplasia and susceptibility to viral infection associated with chronic lung diseases are incompletely understood.
  
  
  OBJECTIVE
  We sought to identify the role of the transcription factor FOXA3 in regulation of goblet cell metaplasia and pulmonary innate immunity.
  
  
  METHODS
  FOXA3 was identified in airways from patients with asthma and chronic obstructive pulmonary disease. We produced transgenic mice conditionally expressing Foxa3 in airway epithelial cells and developed human bronchial epithelial cells expressing Foxa3. Foxa3-regulated genes were identified by immunostaining, Western blotting, and RNA analysis. Direct binding of FOXA3 to target genes was identified by chromatin immunoprecipitation sequencing correlated with RNA sequencing.
  
  
  RESULTS
  FOXA3 was highly expressed in airway goblet cells from patients with asthma and chronic obstructive pulmonary disease. FOXA3 was induced by either IL-13 or rhinovirus. Foxa3 induced goblet cell metaplasia and enhanced expression of a network of genes mediating mucus production. Paradoxically, FOXA3 inhibited rhinovirus-induced IFN production, IRF-3 phosphorylation, and IKKε expression and inhibited viral clearance and expression of genes required for antiviral defenses, including MDA5, RIG-I, TLR3, IRF7/9, and nuclear factor-κB.
  
  
  CONCLUSIONS
  FOXA3 induces goblet cell metaplasia in response to infection or Th2 stimulation. Suppression of IFN signaling by FOXA3 provides a plausible mechanism that may serve to limit ongoing Th1 inflammation during the resolution of acute viral infection; however, inhibition of innate immunity by FOXA3 may contribute to susceptibility to viral infections associated with chronic lung disorders accompanied by chronic goblet cell metaplasia.
authors.affiliation: 1 Perinatal Institute, Division of Neonatology, Perinatal and Pulmonary Biology, and.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Korfhagen
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Karp
authors.forename: Soren
authors.initials: S
authors.lastname: Impey
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Scott H
authors.initials: SH
authors.lastname: Randell
authors.forename: Joseph
authors.initials: J
authors.lastname: Kitzmiller
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Maeda
authors.forename: Hans Michael
authors.initials: HM
authors.lastname: Haitchi
authors.forename: Anusha
authors.initials: A
authors.lastname: Sridharan
authors.forename: Albert P
authors.initials: AP
authors.lastname: Senft
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Whitsett
mesh_terms: D000818:Animals; D001249:Asthma / Q000150:complications / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D004198:Disease Susceptibility; D020397:Goblet Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051543:Hepatocyte Nuclear Factor 3-gamma / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D007372:Interferons / Q000378:metabolism; D008679:Metaplasia; D051379:Mice; D008822:Mice, Transgenic; D010850:Picornaviridae Infections / Q000209:etiology / Q000276:immunology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D012229:Rhinovirus; D017423:Sequence Analysis, RNA; D058408:Th1-Th2 Balance
chemical_list: D015415:Biomarkers; C496505:FOXA3 protein, human; C496506:Foxa3 protein, mouse; D051543:Hepatocyte Nuclear Factor 3-gamma; D007372:Interferons