title: Exposure of airway epithelial cells to Pseudomonas aeruginosa biofilm-derived quorum sensing molecules decrease the activity of the anti-oxidant response element bound by NRF2.
abstract: Chronic bacterial infections in cystic fibrosis lung disease are often characterized by Pseudomonas aeruginosa biofilms that are regulated by bacterial intercellular signals termed quorum sensing (QS), such as N-(3-oxododecanoyl)-l-homoserine lactone (3OC12-HSL). This study reports that biofilm-derived exoproducts decrease the transcriptional activity of the anti-oxidant response element in bronchial epithelial cells. In a live co-culture assay of BEAS-2B cells and P. aeruginosa biofilm, the QS molecule 3OC12-HSL was an important but not sole contributor to the inhibition of basal NRF2 luciferase reporter activity. Moreover, biofilm-derived exoproducts and 3OC12-HSL decrease the expression of endogenous antioxidant response element-regulated genes hemeoxygenase-1 (HO-1) and NAD(P)H Quinone Dehydrogenase-1 (NQO-1) while they increase IL-8 expression. As previously reported, IL-8 expression is partially dependent on p38 MAPK activity, but the inhibitory effect of biofilm QS molecules on HO-1 and NQO-1 expression occurs independently of this protein kinase. Finally, the transfection of CFTRdelF508 but not its wild type counterpart decreases basal, planktonic PsaDM and sulforaphane-driven NRF2 luciferase reporter activity in BEAS-2B cells. Therefore, the presence of quorum sensing molecules derived from bacterial biofilms lowers the transcriptional activity of the anti-oxidant response element, which may contribute to the establishment of chronic bacterial infections, especially in the presence of mutated CFTR. Increasing NRF2 activity may thus be a promising strategy to potentiate anti-biofilm activity in cystic fibrosis lung disease.
authors.affiliation: The Meakins-Christie Laboratories at the Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.
authors.forename: Lucie
authors.initials: L
authors.lastname: Roussel
authors.affiliation: The Meakins-Christie Laboratories at the Research Institute of the McGill University Health Centre, Montréal, Québec, Canada. Electronic address: simon.rousseau@mcgill.ca.
authors.forename: Simon
authors.initials: S
authors.lastname: Rousseau
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000378:metabolism; D061745:Antioxidant Response Elements; D018441:Biofilms; D002460:Cell Line; D003550:Cystic Fibrosis / Q000382:microbiology; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000235:genetics; D006714:Homoserine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics; D008168:Lung / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D011552:Pseudomonas Infections / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000378:metabolism / Q000472:pathogenicity*; D053038:Quorum Sensing / Q000502:physiology*
chemical_list: C508606:CXCL8 protein, human; D016209:Interleukin-8; C109860:N-(3-oxododecanoyl)homoserine lactone; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D006714:Homoserine; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D015107:4-Butyrolactone
keywords: CFTR; Cystic fibrosis; Infection; Oxidant; Transcription; p38 MAPK