Journal
JOURNAL OF INFECTIOUS DISEASES
Volume 213, Issue 8, Pages 1289-1298Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jiw054
Keywords
GM-CSF; Aspergillus; neutrophils; monocytes; ROS
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Funding
- National Institutes of Health (NIH) [R01 AI093808, R21 AI105617]
- NIH/National Cancer Institute Cancer Center [P30 CA008748]
- Burroughs Wellcome Fund (Investigators in the Pathogenesis of Infectious Diseases awards)
- Lucille Castori Center for Microbes, Inflammation and Cancer
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Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine that plays a critical role in regulating myeloid cell host defense. In this study, we demonstrated that GM-CSF signaling plays an essential role in antifungal defense against Aspergillus fumigatus. Mice that lack the GM-CSF receptor beta chain (GM-CSFR beta) developed invasive hyphal growth and exhibited impaired survival after pulmonary challenge with A. fumigatus conidia. GM-CSFR beta signaling regulated the recruitment of inflammatory monocytes to infected lungs, but not the recruitment of effector neutrophils. Cell-intrinsic GM-CSFR beta signaling mediated neutrophil and inflammatory monocyte antifungal activity, because lung GM-CSFR beta(-/-) leukocytes exhibited impaired conidial killing compared with GM-CSFR beta(+/+) counterparts in mixed bone marrow chimeric mice. GM-CSFR beta(-/-) neutrophils exhibited reduced (hydrogenated) nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in vivo. Conversely, administration of recombinant GM-CSF enhanced neutrophil NADPH oxidase function, conidiacidal activity, and lung fungal clearance in A. fumigatus-challenged mice. Thus, our study illustrates the functional role of GM-CSFR beta signaling on lung myeloid cell responses against inhaled A. fumigatus conidia and demonstrates a benefit for systemic GM-CSF administration.
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