title: Granulocyte macrophage-colony stimulating factor induced Zn sequestration enhances macrophage superoxide and limits intracellular pathogen survival.
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.
authors.affiliation: Department of Molecular Genetics, Biochemistry, Microbiology and Immunology, University of Cincinnati, OH 45267, USA; Division of Infectious Diseases, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Subramanian Vignesh
authors.forename: Julio A
authors.initials: JA
authors.lastname: Landero Figueroa
authors.forename: Aleksey
authors.initials: A
authors.lastname: Porollo
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Caruso
authors.forename: George S
authors.initials: GS
authors.lastname: Deepe
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D006056:Golgi Apparatus / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006658:Histoplasma / Q000187:drug effects / Q000276:immunology*; D006660:Histoplasmosis / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D054884:Host-Pathogen Interactions; D006801:Humans; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D008668:Metallothionein / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D019255:NADPH Oxidases / Q000235:genetics / Q000276:immunology; D010588:Phagosomes / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013481:Superoxides / Q000276:immunology / Q000378:metabolism*; D015032:Zinc / Q000276:immunology / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C109053:Slc30a4 protein, mouse; C494087:Stat3 protein, mouse; C472293:ZnT7 protein, mouse; D013481:Superoxides; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D008668:Metallothionein; D019255:NADPH Oxidases; D015032:Zinc