title: Reduced caveolin-1 promotes hyperinflammation due to abnormal heme oxygenase-1 localization in lipopolysaccharide-challenged macrophages with dysfunctional cystic fibrosis transmembrane conductance regulator.
abstract: We have previously reported that TLR4 signaling is increased in LPS-stimulated cystic fibrosis (CF) macrophages (MΦs), contributing to the robust production of proinflammatory cytokines. The heme oxygenase-1 (HO-1)/CO pathway modulates cellular redox status, inflammatory responses, and cell survival. The HO-1 enzyme, together with the scaffold protein caveolin 1 (CAV-1), also acts as a negative regulator of TLR4 signaling in MΦs. In this study, we demonstrate that in LPS-challenged CF MΦs, HO-1 does not compartmentalize normally to the cell surface and instead accumulates intracellularly. The abnormal HO-1 localization in CF MΦs in response to LPS is due to decreased CAV-1 expression, which is controlled by the cellular oxidative state, and is required for HO-1 delivery to the cell surface. Overexpression of HO-1 or stimulating the pathway with CO-releasing molecules enhances CAV-1 expression in CF MΦs, suggesting a positive-feed forward loop between HO-1/CO induction and CAV-1 expression. These manipulations re-established HO-1 and CAV-1 cell surface localization in CF MΦs. Consistent with restoration of HO-1/CAV-1-negative regulation of TLR4 signaling, genetic or pharmacological (CO-releasing molecule 2) induced enhancement of this pathway decreased the inflammatory response of CF MΦs and CF mice treated with LPS. In conclusion, our results demonstrate that the counterregulatory HO-1/CO pathway, which is critical in balancing and limiting the inflammatory response, is defective in CF MΦs through a CAV-1-dependent mechanism, exacerbating the CF MΦ response to LPS. This pathway could be a potential target for therapeutic intervention for CF lung disease.
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06509, USA.
authors.forename: Ping-Xia
authors.initials: PX
authors.lastname: Zhang
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Murray
authors.forename: Valeria R
authors.initials: VR
authors.lastname: Villella
authors.forename: Eleonora
authors.initials: E
authors.lastname: Ferrari
authors.forename: Speranza
authors.initials: S
authors.lastname: Esposito
authors.forename: Anthony
authors.initials: A
authors.lastname: D'Souza
authors.forename: Valeria
authors.initials: V
authors.lastname: Raia
authors.forename: Luigi
authors.initials: L
authors.lastname: Maiuri
authors.forename: Diane S
authors.initials: DS
authors.lastname: Krause
authors.forename: Marie E
authors.initials: ME
authors.lastname: Egan
authors.forename: Emanuela M
authors.initials: EM
authors.lastname: Bruscia
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D051242:Caveolin 1 / Q000096:biosynthesis / Q000378:metabolism*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000276:immunology / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005260:Female; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008171:Lung Diseases / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009298:Nasal Polyps; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D055815:Young Adult
chemical_list: D051242:Caveolin 1; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D051547:Heme Oxygenase-1