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.

Immunity against fungi

“…Similarly, neutralizing IFN-γ and GM-CSF autoantibodies can underlie adult-onset acquired immunodeficiency characterized by endemic dimorphic fungal (143) and CNS cryptococcal disease (144). Patients with alveolar proteinosis due to impaired GM-CSF signaling develop aspergillosis (145), consistent with murine studies (146).…”

Aspergillus fumigatus Copper Export Machinery and Reactive Oxygen Intermediate Defense Counter Host Copper-Mediated Oxidative Antimicrobial Offense

“…Molecular mechanisms by which AMΦ and neutrophils destroy inhaled A. fumigatus spores are only partially understood. Together, these data imply that transition metal homeostasis (mainly iron, copper, and zinc) and production of reactive oxygen intermediates (ROI) are the major strategies employed to kill A. fumigatus conidia (Clark et al, 2016; Dagenais and Keller, 2009; Heinekamp et al, 2015; Kasahara et al, 2016; Lanternier et al, 2013; Park and Mehrad, 2009). …”

Innate Lung Defense during Invasive Aspergillosis: New Mechanisms

“…Recently, it was demonstrated that mice deficient in the receptor for GM-CSF were unable to control infection, primarily as a result of the recruitment of inflammatory monocytes being impaired, but not that of neutrophils. However, the defective generation of ROS and also antifungal activity was exhibited by both cell types [60] . GM-CSF treatment was found to be effective in enhancing neutrophil function and lowering the A. fumigatus lung burden, an effect dependent on the generation of ROS.…”