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(American Journal of Pathology. 2007;170:1028-1040.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060595

Role of Granulocyte Macrophage Colony-Stimulating Factor in Host Defense Against Pulmonary Cryptococcus neoformans Infection during Murine Allergic Bronchopulmonary Mycosis

Gwo-Hsiao Chen*, Michal A. Olszewski*{dagger}, Roderick A. McDonald*, Jason C. Wells*, Robert Paine, III*{dagger}, Gary B. Huffnagle*{ddagger} and Galen B. Toews*{dagger}

From the Division of Pulmonary and Critical Care Medicine,* Department of Internal Medicine, and Department of Microbiology and Immunology,{ddagger} University of Michigan Medical School; and The Veterans Administration Medical Center,{dagger} Ann Arbor, Michigan

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.




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