GM-CSF, via PU.1, regulates alveolar macrophage Fc R-mediated phagocytosis and the IL-18/IFN- –mediated molecular connection between innate and adaptive immunity in the lung

Severely impaired pulmonary microbial clearance was observed in granulocytemacrophage colony-stimulating factor (GM-CSF)–deficient mice. To determine mechanisms by which GM-CSF mediates lung host defense, Fc R-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 Fc R expression. Because interferon(IFN) augments macrophage Fc R levels, the role of GM-CSF/PU.1 in the regulation of AM Fc R expression by IFNwas assessed during adenoviral lung infection. Adenoviral infection stimulated IFNproduction and augmented Fc R levels on AMs in GM-CSF–expressing but not GM / mice. However, IFNexposure ex vivo stimulated Fc R expression on GM / AMs. Because interleukin-18 (IL-18) and IL-12 stimulate IFNproduction during adenoviral infection, their role in GM-CSF/PU.1 regulation of IFN–augmented Fc R 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 IFNproduction and restored Fc R expression on AMs. These results show that GM-CSF, via PU.1, regulates constitutive AM Fc R expression and opsonophagocytosis and is required for the IFN–dependent regulation of AM Fc R expression, enabling AMs to release IL-18/ IL-12 during lung infection. (Blood. 2002; 100:4193-4200)