title: Role of Granulocyte-Macrophage Colony-Stimulating Factor Signaling in Regulating Neutrophil Antifungal Activity and the Oxidative Burst During Respiratory Fungal Challenge.
abstract: 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 β chain (GM-CSFRβ) developed invasive hyphal growth and exhibited impaired survival after pulmonary challenge with A. fumigatus conidia. GM-CSFRβ signaling regulated the recruitment of inflammatory monocytes to infected lungs, but not the recruitment of effector neutrophils. Cell-intrinsic GM-CSFRβ signaling mediated neutrophil and inflammatory monocyte antifungal activity, because lung GM-CSFRβ(-/-) leukocytes exhibited impaired conidial killing compared with GM-CSFRβ(+/+) counterparts in mixed bone marrow chimeric mice. GM-CSFRβ(-/-) 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-CSFRβ signaling on lung myeloid cell responses against inhaled A. fumigatus conidia and demonstrates a benefit for systemic GM-CSF administration.
authors.affiliation: Infectious Disease Service, Department of Medicine.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kasahara
authors.affiliation: Infectious Disease Service, Department of Medicine.
authors.forename: Anupam
authors.initials: A
authors.lastname: Jhingran
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth University, Hanover, New Hampshire.
authors.forename: Sourabh
authors.initials: S
authors.lastname: Dhingra
authors.affiliation: Infectious Disease Service, Department of Medicine.
authors.forename: Anand
authors.initials: A
authors.lastname: Salem
authors.affiliation: Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth University, Hanover, New Hampshire.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cramer
authors.affiliation: Infectious Disease Service, Department of Medicine Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Hohl
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000276:immunology*; D001228:Aspergillosis / Q000276:immunology* / Q000378:metabolism; D001232:Aspergillus fumigatus / Q000276:immunology; D002478:Cells, Cultured; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D018375:Neutrophil Activation; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000276:immunology; D016897:Respiratory Burst / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D000935:Antifungal Agents; D017382:Reactive Oxygen Species; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Aspergillus; GM-CSF; ROS; monocytes; neutrophils