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

Deffert, Christine
Kelkka, Tiina
Holmdahl, Rikard
Schäppi, Michela G
Published in Journal of pathology. 2012, vol. 228, no. 3, p. 341-50
Abstract 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.
Keywords AnimalsAntigens, CD/metabolismAntigens, Differentiation, Myelomonocytic/metabolismCytokines/metabolismDendritic Cells/metabolism/pathologyDisease Models, AnimalGranulomatous Disease, Chronic/metabolism/pathology/prevention & controlInflammation/chemically induced/pathology/prevention & controlMacrophages/metabolism/pathologyMaleMembrane Glycoproteins/genetics/metabolismMiceMice, Mutant StrainsMice, TransgenicNADPH Oxidase/genetics/metabolismNeutrophils/metabolism/pathologyProteoglycans/adverse effectsReactive Oxygen Species/metabolismReceptors, Transforming Growth Factor beta
PMID: 22685019
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Research groups Facteurs influençants le développement pulmonaire: étude translationnelle chez l'animal et l'homme (182)
Groupe Schaller Karl-Lothard (neurochirurgie) (851)
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DEFFERT, Christine et al. Hyperinflammation of chronic granulomatous disease is abolished by NOX2 reconstitution in macrophages and dendritic cells. In: Journal of pathology, 2012, vol. 228, n° 3, p. 341-50. doi: 10.1002/path.4061 https://archive-ouverte.unige.ch/unige:28428

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Deposited on : 2013-06-10

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