p47phox Directs Murine Macrophage Cell Fate Decisions

Macrophage differentiation and function are pivotal for cell survival from infection and involve the processing of microenvironmental signals that determine macrophage cell fate decisions to establish appropriate inflammatory balance. NADPH oxidase 2 (Nox2)–deficient chronic granulomatous disease (CGD) mice that lack the gp91 phox (gp91 phox−/− ) catalytic subunit show high mortality rates compared with wild-type mice when challenged by infection with Listeria monocytogenes ( Lm ), whereas p47 phox -deficient (p47 phox−/− ) CGD mice show survival rates that are similar to those of wild-type mice. We demonstrate that such survival results from a skewed macrophage differentiation program in p47 phox−/− mice that favors the production of higher levels of alternatively activated macrophages (AAMacs) compared with levels of either wild-type or gp91 phox−/− mice. Furthermore, the adoptive transfer of AAMacs from p47 phox−/− mice can rescue gp91 phox−/− mice during primary Lm infection. Key features of the protective function provided by p47 phox−/− AAMacs against Lm infection are enhanced production of IL-1α and killing of Lm . Molecular analysis of this process indicates that p47 phox−/− macrophages are hyperresponsive to IL-4 and show higher Stat6 phosphorylation levels and signaling coupled to downstream activation of AAMac transcripts in response to IL-4 stimulation. Notably, restoring p47 phox protein expression levels reverts the p47 phox -dependent AAMac phenotype. Our results indicate that p47 phox is a previously unrecognized regulator for IL-4 signaling pathways that are important for macrophage cell fate choice.