title: IL-4 Induces Metallothionein 3- and SLC30A4-Dependent Increase in Intracellular Zn(2+) that Promotes Pathogen Persistence in Macrophages.
abstract: Alternative activation of macrophages promotes wound healing but weakens antimicrobial defenses against intracellular pathogens. The mechanisms that suppress macrophage function to create a favorable environment for pathogen growth remain elusive. We show that interleukin (IL)-4 triggers a metallothionein 3 (MT3)- and Zn exporter SLC30A4-dependent increase in the labile Zn(2+) stores in macrophages and that intracellular pathogens can exploit this increase in Zn to survive. IL-4 regulates this pathway by shuttling extracellular Zn into macrophages and by activating cathepsins that act on MT3 to release bound Zn. We show that IL-4 can modulate Zn homeostasis in both human monocytes and mice. In vivo, MT3 can repress macrophage function in an M2-polarizing environment to promote pathogen persistence. Thus, MT3 and SLC30A4 dictate the size of the labile Zn(2+) pool and promote the survival of a prototypical intracellular pathogen in M2 macrophages.
authors.affiliation: 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.affiliation: University of Cincinnati/Agilent Technologies Metallomics Center of the Americas, Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221, USA.
authors.forename: Julio A
authors.initials: JA
authors.lastname: Landero Figueroa
authors.affiliation: Center for Autoimmune Genomics and Etiology and Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Aleksey
authors.initials: A
authors.lastname: Porollo
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Senad
authors.initials: S
authors.lastname: Divanovic
authors.affiliation: University of Cincinnati/Agilent Technologies Metallomics Center of the Americas, Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Caruso
authors.affiliation: Division of Infectious Diseases, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA; Veterans Affairs Hospital, Cincinnati, OH 45220, USA. Electronic address: george.deepe@uc.edu.
authors.forename: George S
authors.initials: GS
authors.lastname: Deepe
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000276:immunology / Q000378:metabolism*; D006660:Histoplasmosis / Q000276:immunology / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000502:physiology*; D006801:Humans; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism*; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D000090023:Metallothionein 3; D051379:Mice; D009419:Nerve Tissue Proteins / Q000276:immunology / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; D000090023:Metallothionein 3; C000715430:Mt3 protein, mouse; D009419:Nerve Tissue Proteins; C491597:SLC30A4 protein, human; D015847:Interleukin-4; D015032:Zinc