title: GM-CSF, via PU.1, regulates alveolar macrophage Fcgamma R-mediated phagocytosis and the IL-18/IFN-gamma -mediated molecular connection between innate and adaptive immunity in the lung.
abstract: Severely impaired pulmonary microbial clearance was observed in granulocyte-macrophage colony-stimulating factor (GM-CSF)-deficient mice. To determine mechanisms by which GM-CSF mediates lung host defense, FcgammaR-mediated phagocytosis (opsonophagocytosis) by alveolar macrophages (AMs) was assessed in GM-CSF-sufficient (GM(+/+)) and -deficient (GM(-/-)) mice and in GM(-/-) mice expressing GM-CSF only in the lungs from a surfactant protein C (SPC) promoter (SPC-GM(+/+)/GM(-/-)). Opsonophagocytosis by GM(-/-) AMs was severely impaired and was restored by pulmonary GM-CSF expression in vivo or by PU.1 expression in vitro. Defective opsonophagocytosis by GM(-/-) AMs was associated with decreased FcgammaR expression. Because interferon-gamma (IFN-gamma) augments macrophage FcgammaR levels, the role of GM-CSF/PU.1 in the regulation of AM FcgammaR expression by IFN-gamma was assessed during adenoviral lung infection. Adenoviral infection stimulated IFN-gamma production and augmented FcgammaR levels on AMs in GM-CSF-expressing but not GM(-/-) mice. However, IFN-gamma exposure ex vivo stimulated FcgammaR expression on GM(-/-) AMs. Because interleukin-18 (IL-18) and IL-12 stimulate IFN-gamma production during adenoviral infection, their role in GM-CSF/PU.1 regulation of IFN-gamma-augmented FcgammaR expression on AMs was assessed. Adenoviral infection stimulated IL-18 and IL-12 production in GM-CSF-expressing mice, but both were markedly reduced or absent in GM(-/-) mice. IL-18 expression by GM(-/-) AMs was severely impaired and was restored by pulmonary GM-CSF expression in vivo or by PU.1 expression in vitro. Pulmonary administration of IL-18 in GM(-/-) mice stimulated IFN-gamma production and restored FcgammaR expression on AMs. These results show that GM-CSF, via PU.1, regulates constitutive AM FcgammaR expression and opsonophagocytosis and is required for the IFN-gamma-dependent regulation of AM FcgammaR expression, enabling AMs to release IL-18/IL-12 during lung infection.
authors.affiliation: Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Berclaz
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shibata
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Whitsett
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Trapnell
mesh_terms: D000257:Adenoviridae Infections / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002460:Cell Line; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D007371:Interferon-gamma / Q000032:analysis; D018664:Interleukin-12 / Q000032:analysis; D020382:Interleukin-18 / Q000032:analysis; D008168:Lung / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis; D011024:Pneumonia, Viral / Q000276:immunology / Q000378:metabolism / Q000821:virology; D011518:Proto-Oncogene Proteins / Q000276:immunology*; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000276:immunology*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D018664:Interleukin-12; D020382:Interleukin-18; D011518:Proto-Oncogene Proteins; D017452:Receptors, IgG; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1