The NADPH Oxidase Nox4 Controls Macrophage Polarization in an NFκB-Dependent Manner

الملخص EN

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.