The NADPH Oxidase Nox4 Controls Macrophage Polarization in an NFB-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 HO 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+IFN) 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/IFN or IL4/IL13 results in polarization of the cells into M(LPS+IFN) or M(IL4+IL13) macrophages, respectively. In this ex vivo setting, Nox4 deficiency reduces M(IL4+IL13) polarization and forces M(LPS+IFN). Nox4-/- M(LPS+IFN)-polarized macrophages express more Nox2 and produce more superoxide anions than wild type M(LPS+IFN)-polarized macrophages. Mechanistically, Nox4 deficiency reduces STAT6 activation and promotes NFB activity, with the latter being responsible for the higher level of Nox2 in Nox4-deficient M(LPS+IFN)-polarized macrophages. According to those findings, , 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 NFB activity in monocytes.