GBA2-encoded β-glucosidase activity is involved in the inflammatory response to Pseudomonas aeruginosa.

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...

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Autores principales:	Nicoletta Loberto, Maela Tebon, Ilaria Lampronti, Nicola Marchetti, Massimo Aureli, Rosaria Bassi, Maria Grazia Giri, Valentino Bezzerri, Valentina Lovato, Cinzia Cantù, Silvia Munari, Seng H Cheng, Alberto Cavazzini, Roberto Gambari, Sandro Sonnino, Giulio Cabrini, Maria Cristina Dechecchi
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4829eaeb20c44aa386679ed5c67b131d
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spelling	oai:doaj.org-article:4829eaeb20c44aa386679ed5c67b131d2021-11-25T06:03:53ZGBA2-encoded β-glucosidase activity is involved in the inflammatory response to Pseudomonas aeruginosa.1932-620310.1371/journal.pone.0104763https://doaj.org/article/4829eaeb20c44aa386679ed5c67b131d2014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25141135/?tool=EBIhttps://doaj.org/toc/1932-6203Current 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.Nicoletta LobertoMaela TebonIlaria LamprontiNicola MarchettiMassimo AureliRosaria BassiMaria Grazia GiriValentino BezzerriValentina LovatoCinzia CantùSilvia MunariSeng H ChengAlberto CavazziniRoberto GambariSandro SonninoGiulio CabriniMaria Cristina DechecchiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 8, p e104763 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Nicoletta Loberto Maela Tebon Ilaria Lampronti Nicola Marchetti Massimo Aureli Rosaria Bassi Maria Grazia Giri Valentino Bezzerri Valentina Lovato Cinzia Cantù Silvia Munari Seng H Cheng Alberto Cavazzini Roberto Gambari Sandro Sonnino Giulio Cabrini Maria Cristina Dechecchi GBA2-encoded β-glucosidase activity is involved in the inflammatory response to Pseudomonas aeruginosa.
description	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.
format	article
author	Nicoletta Loberto Maela Tebon Ilaria Lampronti Nicola Marchetti Massimo Aureli Rosaria Bassi Maria Grazia Giri Valentino Bezzerri Valentina Lovato Cinzia Cantù Silvia Munari Seng H Cheng Alberto Cavazzini Roberto Gambari Sandro Sonnino Giulio Cabrini Maria Cristina Dechecchi
author_facet	Nicoletta Loberto Maela Tebon Ilaria Lampronti Nicola Marchetti Massimo Aureli Rosaria Bassi Maria Grazia Giri Valentino Bezzerri Valentina Lovato Cinzia Cantù Silvia Munari Seng H Cheng Alberto Cavazzini Roberto Gambari Sandro Sonnino Giulio Cabrini Maria Cristina Dechecchi
author_sort	Nicoletta Loberto
title	GBA2-encoded β-glucosidase activity is involved in the inflammatory response to Pseudomonas aeruginosa.
title_short	GBA2-encoded β-glucosidase activity is involved in the inflammatory response to Pseudomonas aeruginosa.
title_full	GBA2-encoded β-glucosidase activity is involved in the inflammatory response to Pseudomonas aeruginosa.
title_fullStr	GBA2-encoded β-glucosidase activity is involved in the inflammatory response to Pseudomonas aeruginosa.
title_full_unstemmed	GBA2-encoded β-glucosidase activity is involved in the inflammatory response to Pseudomonas aeruginosa.
title_sort	gba2-encoded β-glucosidase activity is involved in the inflammatory response to pseudomonas aeruginosa.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/4829eaeb20c44aa386679ed5c67b131d
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GBA2-encoded β-glucosidase activity is involved in the inflammatory response to Pseudomonas aeruginosa.

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