Hyperinflammation of chronic granulomatous disease is abolished by NOX2 reconstitution in macrophages and dendritic cells

Article Article scientifique Article Hyperinflammation of chronic granulomatous disease is abolished by NOX2 reconstitution in macrophages and dendritic cells eng 2012 author Deffert Christine author Carnesecchi Stéphanie 564895 author Yuan Huiping 699986 author Rougemont-Pidoux Anne-Laure 29140 author Kelkka Tiina author Holmdahl Rikard author Krause Karl-Heinz 23022 author Schäppi Michela G 341-350 10.1002/path.4061 22685019 0022-3417 Chronic granulomatous disease (CGD), caused by a lack of reactive oxygen species (ROS) generation by the phagocyte NADPH oxidase NOX2, leads to massively increased inflammatory responses. In order to identify the type of phagocyte which requires NOX2 activity to limit inflammation, we investigated mice with a loss of function mutation in the Ncf1 gene coding for the p47phox subunit of NOX2 and mice with transgenic rescue of Ncf1 under control of the CD68 promoter. To induce CGD hyperinflammation, different mouse genotypes were injected intradermally with β-glucan. Ncf1 mutant mice showed massive and prolonged hyperinflammation. Hyperinflammatory lesions were characterized by persistent neutrophilic infiltration, along with ulceration and necrosis. In contrast, in CD68 promoter rescue mice inflammation resolved within days, as seen in wild-type animals. Measurements of ROS in rescue mice demonstrated functional NOX2 in mononuclear phagocytes (macrophages and dendritic cells) but not in neutrophils. This absence of NOX2 function was also confirmed in inflammatory tissue neutrophils. Lack of functional NOX2 in mononuclear phagocytes increased the secretion of IL-1β at early time points and of IL-6 and TNFα at later time points. Thus, CGD hyperinflammation is a redox dysregulation in mononuclear phagocytes, demonstrating a cell type-specific anti-inflammatory function of NOX2. Animals Antigens, CD/metabolism Antigens, Differentiation, Myelomonocytic/metabolism Cytokines/metabolism Dendritic Cells/metabolism/pathology Disease Models, Animal Granulomatous Disease, Chronic/metabolism/pathology/prevention & control Inflammation/chemically induced/pathology/prevention & control Macrophages/metabolism/pathology Male Membrane Glycoproteins/genetics/metabolism Mice Mice, Mutant Strains Mice, Transgenic NADPH Oxidase/genetics/metabolism Neutrophils/metabolism/pathology Proteoglycans/adverse effects Reactive Oxygen Species/metabolism Receptors, Transforming Growth Factor beta 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 182 513 Groupe Schaller Karl-Lothard (neurochirurgie) 851 Journal of pathology 228 3 7aac55e4-22cb-4237-bba6-5a91d3b5953e Article (Published version) Restricted Rougemont AL J Pathol 2012, 228(3), 341 .pdf 247508 application/pdf restrictedAccess 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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Hyperinflammation of chronic granulomatous disease is abolished by NOX2 reconstitution in macrophages and dendritic cells	Journal of pathology			2012	698	3

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Yuan, Huiping