title: Pseudomonas aeruginosa-induced apoptosis in airway epithelial cells is mediated by gap junctional communication in a JNK-dependent manner.
abstract: Chronic infection and inflammation of the airways is a hallmark of cystic fibrosis (CF), a disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The response of the CF airway epithelium to the opportunistic pathogen Pseudomonas aeruginosa is characterized by altered inflammation and apoptosis. In this study, we examined innate immune recognition and epithelial responses at the level of the gap junction protein connexin43 (Cx43) in polarized human airway epithelial cells upon infection by PAO1. We report that PAO1 activates cell surface receptors to elicit an intracellular signaling cascade leading to enhancement of gap junctional communication. Expression of Cx43 involved an opposite regulation exerted by JNK and p38 MAPKs. PAO1-induced apoptosis was increased in the presence of a JNK inhibitor, but latter effect was prevented by lentiviral expression of a Cx43-specific short hairpin RNA. Moreover, we found that JNK activity was upregulated by pharmacological inhibition of CFTR in Calu-3 cells, whereas correction of a CF airway cell line (CF15 cells) by adenoviral expression of CFTR reduced the activation of this MAPK. Interestingly, CFTR inhibition in Calu-3 cells was associated with decreased Cx43 expression and reduced apoptosis. These results indicate that Cx43 expression is a component of the response of airway epithelial cells to innate immune activation by regulating the survival/apoptosis balance. Defective CFTR could alter this equilibrium with deleterious consequences on the CF epithelial response to P. aeruginosa.
authors.affiliation: Laboratory of Clinical Investigation III, Geneva University Hospitals, 1211 Geneva, Switzerland;
authors.forename: Davide
authors.initials: D
authors.lastname: Losa
authors.forename: Thilo
authors.initials: T
authors.lastname: Köhler
authors.forename: Jessica
authors.initials: J
authors.lastname: Bellec
authors.forename: Tecla
authors.initials: T
authors.lastname: Dudez
authors.forename: Sophie
authors.initials: S
authors.lastname: Crespin
authors.forename: Marc
authors.initials: M
authors.lastname: Bacchetta
authors.forename: Pierre
authors.initials: P
authors.lastname: Boulanger
authors.forename: Saw See
authors.initials: SS
authors.lastname: Hong
authors.forename: Sandrine
authors.initials: S
authors.lastname: Morel
authors.forename: Tuan H
authors.initials: TH
authors.lastname: Nguyen
authors.forename: Christian
authors.initials: C
authors.lastname: van Delden
authors.forename: Marc
authors.initials: M
authors.lastname: Chanson
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D002450:Cell Communication / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D018031:Connexin 43 / Q000235:genetics / Q000276:immunology; D003550:Cystic Fibrosis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology* / Q000473:pathology; D017629:Gap Junctions / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D011552:Pseudomonas Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000276:immunology*; D020545:Respiratory Mucosa / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology
chemical_list: C505032:CFTR protein, human; D018031:Connexin 43; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4