The NADPH Oxidase Nox4 Controls Macrophage Polarization in an NFκB-Dependent Manner
The family of NADPH oxidases represents an important source of reactive oxygen species (ROS) within the cell. Nox4 is a special member of this family as it constitutively produces H2O2 and its loss promotes inflammation. A major cellular component of inflammation is the macrophage population, which...
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Series: | Oxidative Medicine and Cellular Longevity |
Online Access: | http://dx.doi.org/10.1155/2019/3264858 |
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doaj-8b1741d05ea64c3e9c617c2d3a0672612020-11-25T02:12:51ZengHindawi LimitedOxidative Medicine and Cellular Longevity1942-09001942-09942019-01-01201910.1155/2019/32648583264858The NADPH Oxidase Nox4 Controls Macrophage Polarization in an NFκB-Dependent MannerV. Helfinger0K. Palfi1A. Weigert2K. Schröder3Institute for Cardiovascular Physiology, Goethe-University, Frankfurt, GermanyInstitute for Cardiovascular Physiology, Goethe-University, Frankfurt, GermanyInstitute for Biochemistry I, Goethe-University, Frankfurt, GermanyInstitute for Cardiovascular Physiology, Goethe-University, Frankfurt, GermanyThe family of NADPH oxidases represents an important source of reactive oxygen species (ROS) within the cell. Nox4 is a special member of this family as it constitutively produces H2O2 and its loss promotes inflammation. A major cellular component of inflammation is the macrophage population, which can be divided into several subpopulations depending on their phenotype, with proinflammatory M(LPS+IFNγ) and wound-healing M(IL4+IL13) macrophages being extremes of the functional spectrum. Whether Nox4 is expressed in macrophages is discussed controversially. Here, we show that macrophages besides a high level of Nox2 indeed express Nox4. As Nox4 contributes to differentiation of many cells, we hypothesize that Nox4 plays a role in determining the polarization and the phenotype of macrophages. In bone marrow-derived monocytes, ex vivo treatment with LPS/IFNγ or IL4/IL13 results in polarization of the cells into M(LPS+IFNγ) or M(IL4+IL13) macrophages, respectively. In this ex vivo setting, Nox4 deficiency reduces M(IL4+IL13) polarization and forces M(LPS+IFNγ). Nox4-/- M(LPS+IFNγ)-polarized macrophages express more Nox2 and produce more superoxide anions than wild type M(LPS+IFNγ)-polarized macrophages. Mechanistically, Nox4 deficiency reduces STAT6 activation and promotes NFκB activity, with the latter being responsible for the higher level of Nox2 in Nox4-deficient M(LPS+IFNγ)-polarized macrophages. According to those findings, in vivo, in a murine inflammation-driven fibrosarcoma model, Nox4 deficiency forces the expression of proinflammatory genes and cytokines, accompanied by an increase in the number of proinflammatory Ly6C+ macrophages in the tumors. Collectively, the data obtained in this study suggest an anti-inflammatory role for Nox4 in macrophages. Nox4 deficiency results in less M(IL4+IL13) polarization and suppression of NFκB activity in monocytes.http://dx.doi.org/10.1155/2019/3264858 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
V. Helfinger K. Palfi A. Weigert K. Schröder |
spellingShingle |
V. Helfinger K. Palfi A. Weigert K. Schröder The NADPH Oxidase Nox4 Controls Macrophage Polarization in an NFκB-Dependent Manner Oxidative Medicine and Cellular Longevity |
author_facet |
V. Helfinger K. Palfi A. Weigert K. Schröder |
author_sort |
V. Helfinger |
title |
The NADPH Oxidase Nox4 Controls Macrophage Polarization in an NFκB-Dependent Manner |
title_short |
The NADPH Oxidase Nox4 Controls Macrophage Polarization in an NFκB-Dependent Manner |
title_full |
The NADPH Oxidase Nox4 Controls Macrophage Polarization in an NFκB-Dependent Manner |
title_fullStr |
The NADPH Oxidase Nox4 Controls Macrophage Polarization in an NFκB-Dependent Manner |
title_full_unstemmed |
The NADPH Oxidase Nox4 Controls Macrophage Polarization in an NFκB-Dependent Manner |
title_sort |
nadph oxidase nox4 controls macrophage polarization in an nfκb-dependent manner |
publisher |
Hindawi Limited |
series |
Oxidative Medicine and Cellular Longevity |
issn |
1942-0900 1942-0994 |
publishDate |
2019-01-01 |
description |
The family of NADPH oxidases represents an important source of reactive oxygen species (ROS) within the cell. Nox4 is a special member of this family as it constitutively produces H2O2 and its loss promotes inflammation. A major cellular component of inflammation is the macrophage population, which can be divided into several subpopulations depending on their phenotype, with proinflammatory M(LPS+IFNγ) and wound-healing M(IL4+IL13) macrophages being extremes of the functional spectrum. Whether Nox4 is expressed in macrophages is discussed controversially. Here, we show that macrophages besides a high level of Nox2 indeed express Nox4. As Nox4 contributes to differentiation of many cells, we hypothesize that Nox4 plays a role in determining the polarization and the phenotype of macrophages. In bone marrow-derived monocytes, ex vivo treatment with LPS/IFNγ or IL4/IL13 results in polarization of the cells into M(LPS+IFNγ) or M(IL4+IL13) macrophages, respectively. In this ex vivo setting, Nox4 deficiency reduces M(IL4+IL13) polarization and forces M(LPS+IFNγ). Nox4-/- M(LPS+IFNγ)-polarized macrophages express more Nox2 and produce more superoxide anions than wild type M(LPS+IFNγ)-polarized macrophages. Mechanistically, Nox4 deficiency reduces STAT6 activation and promotes NFκB activity, with the latter being responsible for the higher level of Nox2 in Nox4-deficient M(LPS+IFNγ)-polarized macrophages. According to those findings, in vivo, in a murine inflammation-driven fibrosarcoma model, Nox4 deficiency forces the expression of proinflammatory genes and cytokines, accompanied by an increase in the number of proinflammatory Ly6C+ macrophages in the tumors. Collectively, the data obtained in this study suggest an anti-inflammatory role for Nox4 in macrophages. Nox4 deficiency results in less M(IL4+IL13) polarization and suppression of NFκB activity in monocytes. |
url |
http://dx.doi.org/10.1155/2019/3264858 |
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