title: GBA2-encoded β-glucosidase activity is involved in the inflammatory response to Pseudomonas aeruginosa.
abstract: Current anti-inflammatory strategies for the treatment of pulmonary disease in cystic fibrosis (CF) are limited; thus, there is continued interest in identifying additional molecular targets for therapeutic intervention. Given the emerging role of sphingolipids (SLs) in various respiratory disorders, including CF, drugs that selectively target the enzymes associated with SL metabolism are under development. Miglustat, a well-characterized iminosugar-based inhibitor of β-glucosidase 2 (GBA2), has shown promise in CF treatment because it reduces the inflammatory response to infection by P. aeruginosa and restores F508del-CFTR chloride channel activity. This study aimed to probe the molecular basis for the anti-inflammatory activity of miglustat by examining specifically the role of GBA2 following the infection of CF bronchial epithelial cells by P. aeruginosa. We also report the anti-inflammatory activity of another potent inhibitor of GBA2 activity, namely N-(5-adamantane-1-yl-methoxy)pentyl)-deoxynojirimycin (Genz-529648). In CF bronchial cells, inhibition of GBA2 by miglustat or Genz-529648 significantly reduced the induction of IL-8 mRNA levels and protein release following infection by P. aeruginosa. Hence, the present data demonstrate that the anti-inflammatory effects of miglustat and Genz-529648 are likely exerted through inhibition of GBA2.
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, University of Milano, Milano, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Loberto
authors.affiliation: Laboratory of Molecular Pathology, Department of Pathology and Diagnostics, University Hospital of Verona, Verona, Italy.
authors.forename: Maela
authors.initials: M
authors.lastname: Tebon
authors.affiliation: Department of Life Sciences and Biotechnology, Section of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Lampronti
authors.affiliation: Department of Chemistry and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Marchetti
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, University of Milano, Milano, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Aureli
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, University of Milano, Milano, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Bassi
authors.affiliation: Medical Physics Unit, Department of Pathology and Diagnostics, University Hospital of Verona, Verona, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Giri
authors.affiliation: Laboratory of Molecular Pathology, Department of Pathology and Diagnostics, University Hospital of Verona, Verona, Italy.
authors.forename: Valentino
authors.initials: V
authors.lastname: Bezzerri
authors.affiliation: Laboratory of Molecular Pathology, Department of Pathology and Diagnostics, University Hospital of Verona, Verona, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Lovato
authors.affiliation: Laboratory of Molecular Pathology, Department of Pathology and Diagnostics, University Hospital of Verona, Verona, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Cantù
authors.affiliation: Laboratory of Molecular Pathology, Department of Pathology and Diagnostics, University Hospital of Verona, Verona, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Munari
authors.affiliation: Genzyme, a Sanofi Company, Framingham, Massachusetts, United States of America.
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.affiliation: Department of Chemistry and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Cavazzini
authors.affiliation: Department of Life Sciences and Biotechnology, Section of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gambari
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, University of Milano, Milano, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Sonnino
authors.affiliation: Laboratory of Molecular Pathology, Department of Pathology and Diagnostics, University Hospital of Verona, Verona, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Cabrini
authors.affiliation: Laboratory of Molecular Pathology, Department of Pathology and Diagnostics, University Hospital of Verona, Verona, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Dechecchi
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects / Q000201:enzymology / Q000382:microbiology; D003550:Cystic Fibrosis / Q000201:enzymology*; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000382:microbiology; D005962:Glucosylceramidase; D065089:Glycoside Hydrolase Inhibitors / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000201:enzymology* / Q000382:microbiology; D011552:Pseudomonas Infections / Q000201:enzymology* / Q000382:microbiology; D011550:Pseudomonas aeruginosa; D001617:beta-Glucosidase / Q000378:metabolism*
chemical_list: D065089:Glycoside Hydrolase Inhibitors; D017485:1-Deoxynojirimycin; C059896:miglustat; D001617:beta-Glucosidase; C517537:GBA2 protein, human; D005962:Glucosylceramidase