title: NADPH Oxidases Are Essential for Macrophage Differentiation.
abstract: NADPH oxidases (NOXs) are involved in inflammation, angiogenesis, tumor growth, and osteoclast differentiation. However, the role of NOX1 and NOX2 in macrophage differentiation and tumor progression is still elusive. Here we report that NOX1 and NOX2 are critical for the differentiation of monocytes to macrophages, the polarization of M2-type but not M1-type macrophages, and the occurrence of tumor-associated macrophages (TAMs). We found that deletion of both NOX1 and NOX2 led to a dramatic decrease in ROS production in macrophages and resulted in impaired efficiency in monocyte-to-macrophage differentiation and M2-type macrophage polarization. We further showed that NOX1 and NOX2 were critical for the activation of the MAPKs JNK and ERK during macrophage differentiation and that the deficiency of JNK and ERK activation was responsible for the failure of monocyte-to-macrophage differentiation, in turn affecting M2 macrophage polarization. Furthermore, we demonstrated that the decrease in M2 macrophages and TAMs, concomitant with the reduction of cytokine and chemokine secretion, contributed to the delay in wound healing and the inhibition of tumor growth and metastasis in NOX1/2 double knockout mice compared with WT mice. Collectively, these data provide direct evidence that NOX1 and NOX2 deficiency impairs macrophage differentiation and the occurrence of M2-type TAMs during tumor development.
authors.affiliation: From the Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892 and.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.affiliation: From the Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892 and.
authors.forename: Swati
authors.initials: S
authors.lastname: Choksi
authors.affiliation: From the Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892 and.
authors.forename: Jianhui
authors.initials: J
authors.lastname: Qu
authors.affiliation: From the Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892 and.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Jang
authors.affiliation: From the Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892 and.
authors.forename: Moran
authors.initials: M
authors.lastname: Choe
authors.affiliation: the Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242-1109.
authors.forename: Botond
authors.initials: B
authors.lastname: Banfi
authors.affiliation: the Department of Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242-1109.
authors.forename: John F
authors.initials: JF
authors.lastname: Engelhardt
authors.affiliation: From the Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892 and zgliu@helix.nih.gov.
authors.forename: Zheng-Gang
authors.initials: ZG
authors.lastname: Liu
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D018925:Chemokines / Q000235:genetics / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000201:enzymology / Q000276:immunology*; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000276:immunology* / Q000378:metabolism
chemical_list: D018925:Chemokines; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D009247:NADH, NADPH Oxidoreductases; C488842:Cybb protein, mouse; D000074624:NADPH Oxidase 1; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C000614711:NOX1 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: NADPH oxidase; cell biology; cell differentiation; macrophage; reactive oxygen species (ROS)