title: Cysteamine re-establishes the clearance of Pseudomonas aeruginosa by macrophages bearing the cystic fibrosis-relevant F508del-CFTR mutation.
abstract: Cystic fibrosis (CF), the most common lethal monogenic disease in Caucasians, is characterized by recurrent bacterial infections and colonization, mainly by Pseudomonas aeruginosa, resulting in unresolved airway inflammation. CF is caused by mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which functions as a chloride channel in epithelial cells, macrophages, and other cell types. Impaired bacterial handling by macrophages is a feature of CF airways, although it is still debated how defective CFTR impairs bacterial killing. Recent evidence indicates that a defective autophagy in CF macrophages leads to alterations of bacterial clearance upon infection. Here we use bone marrow-derived macrophages from transgenic mice to provide the genetic proof that defective CFTR compromises both uptake and clearance of internalized Pseudomonas aeruginosa. We demonstrate that the proteostasis regulator cysteamine, which rescues the function of the most common F508del-CFTR mutant and hence reduces lung inflammation in CF patients, can also repair the defects of CF macrophages, thus restoring both bacterial internalization and clearance through a process that involves upregulation of the pro-autophagic protein Beclin 1 and re-establishment of the autophagic pathway. Altogether these results indicate that cysteamine restores the function of several distinct cell types, including that of macrophages, which might contribute to its beneficial effects on CF.
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, European Institute for Research in Cystic Fibrosis, Milan 20132, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Ferrari
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, European Institute for Research in Cystic Fibrosis, Milan 20132, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Monzani
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, European Institute for Research in Cystic Fibrosis, Milan 20132, Italy.
authors.forename: Valeria R
authors.initials: VR
authors.lastname: Villella
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, European Institute for Research in Cystic Fibrosis, Milan 20132, Italy.
authors.forename: Speranza
authors.initials: S
authors.lastname: Esposito
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, European Institute for Research in Cystic Fibrosis, Milan 20132, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Saluzzo
authors.affiliation: Department of Biology, University of Rome 'Tor Vergata', Rome, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Rossin
authors.affiliation: Department of Biology, University of Rome 'Tor Vergata', Rome, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: D'Eletto
authors.affiliation: Regional Cystic Fibrosis Center, Pediatric Unit, Department of Translational Medical Sciences, FedericoII University Naples 80131, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Tosco
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, European Institute for Research in Cystic Fibrosis, Milan 20132, Italy.|Regional Cystic Fibrosis Center, Pediatric Unit, Department of Translational Medical Sciences, FedericoII University Naples 80131, Italy.
authors.forename: Fabiola
authors.initials: F
authors.lastname: De Gregorio
authors.affiliation: Equipe11 labellisée Ligue Nationale contrele Cancer, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Valentina
authors.initials: V
authors.lastname: Izzo
authors.affiliation: Equipe11 labellisée Ligue Nationale contrele Cancer, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Maiuri
authors.affiliation: Equipe11 labellisée Ligue Nationale contrele Cancer, Centre de Recherche des Cordeliers, Paris, France.|INSERM U1138, Centre de Recherche des Cordeliers, Paris, France.|Université Paris Descartes, Paris, France.|Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France.|Pôlede Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, Franceand.|Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm 17176, Sweden.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: Regional Cystic Fibrosis Center, Pediatric Unit, Department of Translational Medical Sciences, FedericoII University Naples 80131, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Raia
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, European Institute for Research in Cystic Fibrosis, Milan 20132, Italy.|SCDU of Pediatrics, Department of Health Sciences, University of Piemonte Orientale, Novara 28100, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Maiuri
mesh_terms: D000818:Animals; D000071186:Beclin-1 / Q000096:biosynthesis / Q000235:genetics*; D001854:Bone Marrow Cells / Q000378:metabolism / Q000382:microbiology; D003543:Cysteamine / Q000008:administration & dosage; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics / Q000382:microbiology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000382:microbiology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000235:genetics / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000472:pathogenicity
chemical_list: D000071186:Beclin-1; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D003543:Cysteamine