Granulocyte Macrophage-Colony Stimulating Factor Induced Zn Sequestration Enhances Macrophage Superoxide and Limits Intracellular Pathogen Survival
Open accessAbstract
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.
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GM-CSF induced expression of two zinc transport proteins leading to accumulation of zinc in the Golgi apparatus, which triggered formation of toxic radicals by NADPH-oxidase and exerted anti-fungal activity against Histoplasma capsulatum.
“Specifically, GM-CSF induced the expression of two zinc transport proteins leading to accumulation of the metal in the Golgi apparatus, which triggered the formation of toxic radicals by NADPH-oxidase and thereby exerting anti-fungal activity against Histoplasma capsulatum (241).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [241]
GM-CSF induces sequestration of zinc in macrophages.
“Recent evidence suggests that granulocyte macrophage colony-stimulating factor (GM-CSF) induces the sequestration of zinc in MΦs.”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [241]
Iron and other components of nutritional immunity (e.g., zinc) regulate essential metabolic and inflammatory pathways in immune cells.
“iron and other components of nutritional immunity (e.g., zinc) regulate essential metabolic and inflammatory pathways in immune cells that are largely uncharacterized (365, 599).”
From Aspergillus fumigatus and Aspergillosis in 2019 (2019) · cites this paper as [599]
Iron and other components of nutritional immunity regulate essential metabolic and inflammatory pathways in immune cells that are largely uncharacterized.
“apart from inhibiting pathogen growth, iron and other components of nutritional immunity (e.g., zinc) regulate essential metabolic and inflammatory pathways in immune cells that are largely uncharacterized (365, 599).”
From Aspergillus fumigatus and Aspergillosis in 2019 (2019) · cites this paper as [599]
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- Authors
- Subramanian Vignesh, K., Landero Figueroa, J. A., Porollo, A., Caruso, J. A., & Deepe, G. S.
- Affiliations
- University of Cincinnati (US)
- Veterans Health Administration (US)
- Corresponding author
- Deepe, George S.
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 39
- Issue
- 4
- Pages
- 697-710
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC3841917
- OpenAlex
- W2011515525
- Cited by
- 230
- References
- 43
- Citations by year
- 2026: 11 · 2025: 7 · 2024: 17 · 2023: 14 · 2022: 19 · 2021: 24 · 2020: 21 · 2019: 21 · 2018: 16 · 2017: 32 · 2016: 14 · 2015: 14 · 2014: 14 · 2013: 5 · 2012: 1
- FWCI
- 11.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Veterans Affairs
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (AI106269, R21AI094971, R01AI083313, AI-094971, R01AI106269)
- Topics
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- GM-CSF, zinc sequestration, metallothionein, macrophages, Histoplasma capsulatum, phagosome, NADPH oxidase, reactive oxygen species, STAT3, STAT5, Golgi apparatus, antimicrobial defense
- MeSH terms
- Animals, Gene Expression Regulation, Golgi Apparatus, Histoplasma, Histoplasmosis, Humans, Macrophage Activation, Metallothionein, Mice, Transgenic, Phagosomes, Superoxides, Zinc, Signal Transduction, Granulocyte-Macrophage Colony-Stimulating Factor, Macrophages, Peritoneal, NADPH Oxidases, Cation Transport Proteins, STAT3 Transcription Factor, STAT5 Transcription Factor, Mice, Host-Pathogen Interactions
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