title: Mutations of Cystic Fibrosis Transmembrane Conductance Regulator Gene Cause a Monocyte-Selective Adhesion Deficiency.
abstract: Cystic fibrosis (CF) is a common genetic disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Persistent lung inflammation, characterized by increasing polymorphonuclear leukocyte recruitment, is a major cause of the decline in respiratory function in patients with CF and is a leading cause of morbidity and mortality. CFTR is expressed in various cell types, including leukocytes, but its involvement in the regulation of leukocyte recruitment is unknown.
  
  
  
  We evaluated whether CF leukocytes might present with alterations in cell adhesion and migration, a key process governing innate and acquired immune responses.
  
  
  
  We used ex vivo adhesion and chemotaxis assays, flow cytometry, immunofluorescence, and GTPase activity assays in this study.
  
  
  
  We found that chemoattractant-induced activation of β1 and β2 integrins and of chemotaxis is defective in mononuclear cells isolated from patients with CF. In contrast, polymorphonuclear leukocyte adhesion and chemotaxis were normal. The functionality of β1 and β2 integrins was restored by treatment of CF monocytes with the CFTR-correcting drugs VRT325 and VX809. Moreover, treatment of healthy monocytes with the CFTR inhibitor CFTR(inh)-172 blocked integrin activation by chemoattractants. In a murine model of lung inflammation, we found that integrin-independent migration of CF monocytes into the lung parenchyma was normal, whereas, in contrast, integrin-dependent transmigration into the alveolar space was impaired. Finally, signal transduction analysis showed that, in CF monocytes, chemoattractant-triggered activation of RhoA and CDC42 Rho small GTPases (controlling integrin activation and chemotaxis, respectively) was strongly deficient.
  
  
  
  Altogether, these data highlight the critical regulatory role of CFTR in integrin activation by chemoattractants in monocytes and identify CF as a new, cell type-selective leukocyte adhesion deficiency disease, providing new insights into CF pathogenesis.
authors.affiliation: 1 Division of General Pathology, Department of Medicine, and.|2 Cystic Fibrosis Translational Research Laboratory "Daniele Lissandrini," Department of Medicine, University of Verona School of Medicine, Verona, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Sorio
authors.affiliation: 1 Division of General Pathology, Department of Medicine, and.
authors.forename: Alessio
authors.initials: A
authors.lastname: Montresor
authors.affiliation: 1 Division of General Pathology, Department of Medicine, and.|2 Cystic Fibrosis Translational Research Laboratory "Daniele Lissandrini," Department of Medicine, University of Verona School of Medicine, Verona, Italy.|3 Department of Tumor Immunology (278), Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Matteo
authors.initials: M
authors.lastname: Bolomini-Vittori
authors.affiliation: 1 Division of General Pathology, Department of Medicine, and.|2 Cystic Fibrosis Translational Research Laboratory "Daniele Lissandrini," Department of Medicine, University of Verona School of Medicine, Verona, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Caldrer
authors.affiliation: 1 Division of General Pathology, Department of Medicine, and.
authors.forename: Barbara
authors.initials: B
authors.lastname: Rossi
authors.affiliation: 1 Division of General Pathology, Department of Medicine, and.
authors.forename: Silvia
authors.initials: S
authors.lastname: Dusi
authors.affiliation: 1 Division of General Pathology, Department of Medicine, and.
authors.forename: Stefano
authors.initials: S
authors.lastname: Angiari
authors.affiliation: 1 Division of General Pathology, Department of Medicine, and.|2 Cystic Fibrosis Translational Research Laboratory "Daniele Lissandrini," Department of Medicine, University of Verona School of Medicine, Verona, Italy.
authors.forename: Jan E
authors.initials: JE
authors.lastname: Johansson
authors.affiliation: 1 Division of General Pathology, Department of Medicine, and.|2 Cystic Fibrosis Translational Research Laboratory "Daniele Lissandrini," Department of Medicine, University of Verona School of Medicine, Verona, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Vezzalini
authors.affiliation: 4 Faculté de Pharmacie et des Sciences Biomédicales, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium; and.
authors.forename: Teresinha
authors.initials: T
authors.lastname: Leal
authors.affiliation: 1 Division of General Pathology, Department of Medicine, and.|2 Cystic Fibrosis Translational Research Laboratory "Daniele Lissandrini," Department of Medicine, University of Verona School of Medicine, Verona, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Calcaterra
authors.affiliation: 5 Centro Fibrosi Cistica, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy.
authors.forename: Baroukh M
authors.initials: BM
authors.lastname: Assael
authors.affiliation: 5 Centro Fibrosi Cistica, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Melotti
authors.affiliation: 1 Division of General Pathology, Department of Medicine, and.
authors.forename: Carlo
authors.initials: C
authors.lastname: Laudanna
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*
chemical_list: D019005:Cystic Fibrosis Transmembrane Conductance Regulator
keywords: cell adhesion; cystic fibrosis; integrins; leukocyte trafficking; lung inflammation