p47(phox) 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.
Molecular Trafficking Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
Liang
L
Yi
Molecular Trafficking Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
Qi
Q
Liu
Infectious Disease Pathogenesis Section, Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
Marlene S
MS
Orandle
Molecular Trafficking Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
Sara
S
Sadiq-Ali
Molecular Trafficking Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
Sherry M
SM
Koontz
Genetic Immunotherapy Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
Uimook
U
Choi
Foreign Animal Disease Diagnostic Lab, Plum Island Animal Disease Center, United States Department of Agriculture, Greenport, New York.
Fernando J
FJ
Torres-Velez
Molecular Trafficking Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland. Electronic address: sjackson@niaid.nih.gov.
Sharon H
SH
Jackson
D019264:Adoptive Transfer; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D005822:Genetic Vectors; D006105:Granulomatous Disease, Chronic / Q000473:pathology; D053582:Interleukin-1alpha / Q000096:biosynthesis / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008089:Listeria monocytogenes; D008088:Listeriosis / Q000473:pathology*; D008262:Macrophage Activation / Q000502:physiology; D008264:Macrophages / Q000166:cytology* / Q000502:physiology; D008562:Membrane Glycoproteins / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency* / Q000502:physiology*; D010587:Phagocytosis / Q000502:physiology; D010766:Phosphorylation; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D016019:Survival Analysis
D053582:Interleukin-1alpha; D008562:Membrane Glycoproteins; D050800:STAT6 Transcription Factor; D015847:Interleukin-4; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1