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IL-4 Induces Metallothionein 3- and SLC30A4-Dependent Increase in Intracellular Zn(2+) that Promotes Pathogen
Kavitha Subramanian Vignesh1, Julio A Landero Figueroa2, Aleksey Porollo3
1Division of Infectious Diseases, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
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.
Insights
Interleukin-4 (IL-4) increases macrophage zinc (Zn) stores via metallothionein 3 (MT3) and SLC30A4, aiding pathogen survival. This mechanism suppresses immune defenses, creating a favorable environment for intracellular pathogens.
Area of Science:
- Immunology
- Cell Biology
- Pathogen-Host Interactions
Background:
- Alternative macrophage activation (M2) enhances wound healing but impairs defenses against intracellular pathogens.
- Mechanisms underlying suppressed macrophage function during infection are not fully understood.
Purpose of the Study:
- To investigate how intracellular pathogens exploit macrophage function.
- To elucidate the role of zinc (Zn) homeostasis in M2 macrophage-mediated immune suppression.
Main Methods:
- Investigated the effects of interleukin-4 (IL-4) on macrophage Zn levels in human monocytes and mice.
- Utilized metallothionein 3 (MT3) and Zn exporter SLC30A4 in mechanistic studies.
- Assessed pathogen survival in M2-polarized macrophages.
Main Results:
- IL-4 induces an increase in labile Zn(2+) stores in macrophages via MT3 and SLC30A4.
- Intracellular pathogens leverage elevated Zn(2+) for survival.
- MT3 represses M2 macrophage function, promoting pathogen persistence in vivo.
Conclusions:
- MT3 and SLC30A4 control the labile Zn(2+) pool in M2 macrophages.
- This Zn(2+) dysregulation promotes intracellular pathogen survival by impairing macrophage antimicrobial activity.
