Role of granulocyte macrophage colony-stimulating factor in host defense against pulmonary Cryptococcus neoformans infection during murine allergic bronchopulmonary mycosis.
We investigated the role of granulocyte macrophage colony-stimulating factor (GM-CSF) in host defense in a murine model of pulmonary cryptococcosis induced by intratracheal inoculation of Cryptococcus neoformans. Pulmonary C. neoformans infection of C57BL/6 mice is an established model of an allergic bronchopulmonary mycosis. Our objective was to determine whether GM-CSF regulates the pulmonary Th2 immune response in C. neoformans-infected C57BL/6 mice. Long-term pulmonary fungistasis was lost in GM-CSF knockout (GM(-/-)) mice, resulting in increased pulmonary burden of fungi between weeks 3 and 5. GM-CSF was required for the early influx of macrophages and CD4 and CD8 T cells into the lungs but was not required later in the infection. Lack of GM-CSF also resulted in reduced eosinophil recruitment and delayed recruitment of mononuclear cells into the airspace. Macrophages from GM(+/+) mice showed numerous hallmarks of alternatively activated macrophages: higher numbers of intracellular cryptococci, YM1 crystals, and induction of CCL17. These hallmarks are absent in macrophages from GM(-/-) mice. Mucus-producing goblet cells were abundantly present within the bronchial epithelial layer in GM(+/+) mice but not in GM(-/-) mice at week 5 after infection. Production of both Th1 and Th2 cytokines was impaired in the absence of GM-CSF, consistent with both reduced C. neoformans clearance and absence of allergic lung pathology.
Chen
Gwo-Hsiao
GH
Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, MI 48109-0642, USA. gchen@umich.edu
Olszewski
Michal A
MA
McDonald
Roderick A
RA
Wells
Jason C
JC
Paine
Robert
R
Huffnagle
Gary B
GB
Toews
Galen B
GB
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D003453:Cryptococcosis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003455:Cryptococcus neoformans / Q000276:immunology; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology* / Q000378:metabolism; D008172:Lung Diseases, Fungal / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
D016178:Granulocyte-Macrophage Colony-Stimulating Factor