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Division of Pulmonary Biology, Childrens Hospital Medical Center, Cincinnati, OH 45229.
GM-CSF gene-targeted (GM-/-) mice have impaired
pulmonary clearance of bacterial and fungal pathogens by alveolar
macrophages (AMs). Because AMs also clear adenovirus from the lung, the
role of GM-CSF in endocytic internalization of adenovirus by AMs was
evaluated. Pulmonary clearance of adenovirus was severely impaired in
GM-/- mice compared to wild-type (GM+/+) mice
as determined by Southern analysis of viral DNA. Internalization of
adenovirus by AMs was deficient in GM-/- mice in vivo and
in vitro as determined by uptake of fluorescently labeled
adenovirus or by PCR quantification of adenoviral DNA internalized
within AMs. An AM cell line previously established from
GM-/- mice (mAM) had impaired internalization of
adenovirus and transferrin-coated 100-nm latex beads compared to
MH-S, a GM+/+ AM cell line. Phagocytosis of 4-µm latex
beads was also impaired in mAM cells as determined by confocal and
fluorescence microscopy. Retroviral vector-mediated reconstitution of
PU.1 expression in cultured GM-/- AMs restored
phagocytosis of 4-µm beads, endocytosis of adenovirus, and
transferrin-coated 100-nm beads (independent of integrin
V and transferrin receptors, respectively), and restored
normal cytoskeletal organization, filamentous actin
distribution, and stimulated formation of filopodia. Interestingly,
mRNA for the phosphoinositide 3 kinase p110
isoform, important in
macrophage phagocytic function, was absent in GM-/- AMs
and was restored by PU.1 expression. These data show that GM-CSF, via
PU.1, regulates endocytosis of small (
100 nm) pathogens/inert
particles and phagocytosis of very large inert particles and suggests
regulation of cytoskeletal organization by GM-CSF/PU.1 as the molecular
basis of this control.
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