Macrophage-specific NOX2 contributes to the development of lung emphysema through modulation of SIRT1/MMP-9 pathways

Article Article scientifique Article Macrophage-specific NOX2 contributes to the development of lung emphysema through modulation of SIRT1/MMP-9 pathways eng 2015 author Trocme Candice author Deffert Christine author Cachat Julien 741234 author Donati Yves Richard 24165 author Tissot Christelle 669442 author Papacatzis Sylvie author Braunersreuther Vincent 510607 author Pache Jean-Claude 513830 author Krause Karl-Heinz 23022 author Holmdahl Rikard author Barazzone Constance 29124 author Carnesecchi Stéphanie 564895 65-78 10.1002/path.4423 25116588 0022-3417 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. Animals Humans Inflammation/pathology Lung/pathology Macrophages/metabolism/pathology Matrix Metalloproteinase 9/metabolism Membrane Glycoproteins/metabolism Mice NADPH Oxidase/metabolism Neutrophils/pathology Pulmonary Emphysema/metabolism/pathology Reactive Oxygen Species/metabolism Sirtuin 1/metabolism Dewey 616.07 Dewey 618 137 Département de pathologie et immunologie 21F 58 Département de pédiatrie, gynécologie et obstétrique 223 false 148 Facteurs influençants le développement pulmonaire: étude translationnelle chez l'animal et l'homme 182 392 Groupe Pache Jean-Claude (pathologie clinique) 658 38 Radicaux libres et cellules souches embryonnaires 60 Journal of pathology 235 1 db196b93-57fe-4dc2-98ce-c8841c5c9096 Article (Published version) Public path0235-0065.pdf 3752040 application/pdf openAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté de médecine / Section de médecine clinique / Département de pédiatrie, gynécologie et obstétrique

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Macrophage-specific NOX2 contributes to the development of lung emphysema through modulation of SIRT1/MMP-9 pathways	Journal of pathology			2015	965	398

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Tissot, Christelle