Title: IL-4 Induces Metallothionein 3- and SLC30A4-Dependent Increase in Intracellular Zn(2+) that Promotes Pathogen Persistence in Macrophages.

Authors: Subramanian Vignesh, Kavitha; Landero Figueroa, Julio A; Porollo, Aleksey; Divanovic, Senad; Caruso, Joseph A; Deepe Jr, George S

Published In Cell Rep, (2016 09 20)

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.

PubMed ID: 27653687

MeSH Terms: Animals; Cation Transport Proteins/immunology; Cation Transport Proteins/metabolism*; Histoplasmosis/immunology; Histoplasmosis/metabolism; Host-Pathogen Interactions/physiology*; Humans; Interleukin-4/immunology; Interleukin-4/metabolism*; Macrophage Activation/immunology; Macrophages/immunology; Macrophages/metabolism; Macrophages/microbiology*; Mice; Nerve Tissue Proteins/immunology; Nerve Tissue Proteins/metabolism*; Zinc/metabolism*