title: Macrophage-specific NOX2 contributes to the development of lung emphysema through modulation of SIRT1/MMP-9 pathways.
abstract: Reactive oxygen species (ROS) participate in the pathogenesis of emphysema. Among ROS-producing enzymes, NOX NADPH oxidases are thought to be responsible for tissue injury associated with several lung pathologies. To determine whether NOX2 and/or NOX1 participate in the development of emphysema, their expression patterns were first studied by immunohistochemistry in the lungs of emphysematous patients. Subsequently, we investigated their contribution to elastase-induced emphysema using NOX2- and NOX1-deficient mice. In human lung, NOX2 was mainly detected in macrophages of control and emphysematous lungs, while NOX1 was expressed in alveolar epithelium and bronchial cells. We observed an elevated number of NOX2-positive cells in human emphysematous lungs, as well as increased NOX2 and NOX1 mRNA expression in mouse lungs following elastase exposure. Elastase-induced alveolar airspace enlargement and elastin degradation were prevented in NOX2-deficient mice, but not in NOX1-deficient mice. This protection was independent of inflammation and correlated with reduced ROS production. Concomitantly, an elevation of sirtuin 1 (SIRT1) level and a decrease of matrix metalloproteinase-9 (MMP-9) expression and activity were observed in alveolar macrophages and neutrophils. We addressed the specific role of macrophage-restricted functional NOX2 in elastase-induced lung emphysema using Ncf1 mutant mice and Ncf1 macrophage rescue mice (Ncf1 mutant mice with transgenic expression of Ncf1 only in CD68-positive mononuclear phagocytes; the MN mouse). Compared to WT mice, the lack of functional NOX2 led to decreased elastase-induced ROS production and protected against emphysema. In contrast, ROS production was restored specifically in macrophages from Ncf1 rescue mice and contributes to emphysema. Taken together, our results demonstrate that NOX2 is involved in the pathogenesis of human emphysema and macrophage-specific NOX2 participates in elastase-induced emphysema through the involvement of SIRT1/MMP-9 pathways in mice.
authors.affiliation: Laboratory of Protein and Enzyme Biochemistry, University Hospital, Grenoble, France.
authors.forename: Candice
authors.initials: C
authors.lastname: Trocme
authors.forename: Christine
authors.initials: C
authors.lastname: Deffert
authors.forename: Julien
authors.initials: J
authors.lastname: Cachat
authors.forename: Yves
authors.initials: Y
authors.lastname: Donati
authors.forename: Christelle
authors.initials: C
authors.lastname: Tissot
authors.forename: Sylvie
authors.initials: S
authors.lastname: Papacatzis
authors.forename: Vincent
authors.initials: V
authors.lastname: Braunersreuther
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Pache
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Krause
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
authors.forename: Constance
authors.initials: C
authors.lastname: Barazzone-Argiroffo
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Carnesecchi
mesh_terms: D000818:Animals; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008168:Lung / Q000473:pathology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D009504:Neutrophils / Q000473:pathology; D011656:Pulmonary Emphysema / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; C056558:CYBB protein, human; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D056564:Sirtuin 1
keywords: MMP-9; NOX2; ROS; SIRT1; emphysema; macrophages