GM-CSF, via PU.1, regulates alveolar macrophage FcγR-mediated phagocytosis and the IL-18/IFN-γ-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, FcγR-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 FcγR expression. Because interferon-γ (IFN-γ) augments macrophage FcγR levels, the role of GM-CSF/PU.1 in the regulation of AM FcγR expression by IFN-γ was assessed during adenoviral lung infection. Adenoviral infection stimulated IFN-γ production and augmented FcγR levels on AMs in GM-CSF-expressing but not GM-/- mice. However, IFN-γ exposure ex vivo stimulated FcγR expression on GM-/- AMs. Because interleukin-18 (IL-18) and IL-12 stimulate IFN-γ production during adenoviral infection, their role in GM-CSF/PU.1 regulation of IFN-γ-augmented FcγR 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-γ production and restored FcγR expression on AMs. These results show that GM-CSF, via PU.1, regulates constitutive AM FcγR expression and opsonophagocytosis and is required for the IFN-γ-dependent regulation of AM FcγR expression, enabling AMs to release IL-18/ IL-12 during lung infection. © 2002 by The American Society of Hematology.