Abstract
Macrophages possess numerous mechanisms to combat microbial invasion, including sequestration of essential nutrients, like zinc (Zn). The pleiotropic cytokine granulocyte macrophage-colony stimulating factor (GM-CSF) enhances antimicrobial defenses against intracellular pathogens such as Histoplasma capsulatum, but its mode of action remains elusive. We have found that GM-CSF-activated infected macrophages sequestered labile Zn by inducing binding to metallothioneins (MTs) in a STAT3 and STAT5 transcription-factor-dependent manner. GM-CSF upregulated expression of Zn exporters, Slc30a4 and Slc30a7; the metal was shuttled away from phagosomes and into the Golgi apparatus. This distinctive Zn sequestration strategy elevated phagosomal H⁺ channel function and triggered reactive oxygen species generation by NADPH oxidase. Consequently, H. capsulatum was selectively deprived of Zn, thereby halting replication and fostering fungal clearance. GM-CSF mediated Zn sequestration via MTs in vitro and in vivo in mice and in human macrophages. These findings illuminate a GM-CSF-induced Zn-sequestration network that drives phagocyte antimicrobial effector function.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cation Transport Proteins / genetics
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Cation Transport Proteins / immunology
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Gene Expression Regulation
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Golgi Apparatus / drug effects
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Golgi Apparatus / immunology
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Golgi Apparatus / microbiology
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Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology*
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Histoplasma / drug effects
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Histoplasma / immunology*
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Histoplasmosis / immunology
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Histoplasmosis / metabolism*
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Histoplasmosis / microbiology
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Host-Pathogen Interactions
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Humans
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Macrophage Activation
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Macrophages, Peritoneal / drug effects
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Macrophages, Peritoneal / immunology*
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Macrophages, Peritoneal / microbiology
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Metallothionein / genetics
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Metallothionein / immunology
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Mice
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Mice, Transgenic
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NADPH Oxidases / genetics
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NADPH Oxidases / immunology
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Phagosomes / drug effects
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Phagosomes / immunology
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Phagosomes / microbiology
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / immunology
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STAT5 Transcription Factor / genetics
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STAT5 Transcription Factor / immunology
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Signal Transduction
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Superoxides / immunology
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Superoxides / metabolism*
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Zinc / immunology
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Zinc / metabolism*
Substances
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Cation Transport Proteins
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STAT3 Transcription Factor
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STAT5 Transcription Factor
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Slc30a4 protein, mouse
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Stat3 protein, mouse
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ZnT7 protein, mouse
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Superoxides
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Granulocyte-Macrophage Colony-Stimulating Factor
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Metallothionein
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NADPH Oxidases
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Zinc