Proposed model for regulation of FcγR-mediated phagocytosis in resting and activated AMs.

In GM^+/+ mice, GM-CSF is released constitutively by respiratory epithelium and other cells in the lung and interacts with receptors on AM precursors, maintaining the presence of the transcription factor PU.1 in AMs. High levels of PU.1 in AMs promote their terminal differentiation,20 including stimulation of expression of FcγRs, thus enabling constitutive FcγR-mediated phagocytosis. Exposure to pathogens such as adenovirus stimulates AMs to release IL-18 and IL-12, both of which are potent stimulators of IFN-γ release by T_H1 and NK cells during adenovirus infection of the respiratory tract.30 IFN-γ then interacts with receptors on AMs and stimulates increased FcγR expression, resulting in increased FcγR-mediated phagocytosis. In GM^−/− mice, PU.1 levels in AMs are deficient due to the absence of GM-CSF in the lungs.20 Because IL-18 expression in AMs requires PU.1, pathogen exposure of AMs in the lungs of GM^−/− mice does not result in release of IL-18. Although NK cells from GM^−/− mice are capable of cytokine-stimulated IFN-γ release,32 in the absence of such a stimulus IFN-γ release does not occur in pathogen-exposed GM^−/− mice and thus is not present to stimulate FcγR or FcγR-mediated phagocytosis by AMs.