[PDF][PDF] IL-4 induces metallothionein 3-and SLC30A4-dependent increase in intracellular Zn2+ that promotes pathogen persistence in macrophages
Cell reports, 2016•cell.com
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 …
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 …
Summary
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 Zn2+ 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 Zn2+ pool and promote the survival of a prototypical intracellular pathogen in M2 macrophages.
cell.com