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

Abstract

SUMMARYAlternative 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.

Alveolar Macrophages in the Resolution of Inflammation, Tissue Repair, and Tolerance to Infection

“…Other metal metabolism can be “highjacked” by pathogens, such as zinc. Vignesh et al have shown that IL-4, a well known M2-polarizing signals, alters macrophage zinc homeostasis via metallothionein 3 and the zinc transporter SLC30A4, promoting pathogen persistence in M2 macrophages ( 75 ).…”

TLR-Induced IL-12 and CCL2 Production by Myeloid Cells Is Dependent on Adenosine A3 Receptor–Mediated Signaling

“…cysteine-rich proteins that regulate intracellular zinc homeostasis, detoxify heavy metals, and counteract superoxide stress (21). Their expression is potently induced by metal exposure and oxidative stress but also by cytokine signaling and microbial challenge (22)(23)(24)(25). In myeloid cells, there is ample evidence for an important role of metallothioneins in the maintenance of intracellular zinc homoeostasis (26)(27)(28).…”

Environmental Cadmium Enhances Lung Injury by Respiratory Syncytial Virus Infection

“…Interaction of IL-4 with Zn has been previously reported via mechanisms dependent on metallothioneins and metal transporter. 56,57 Interestingly, it was shown that increase in Zn may promote pathogen persistence in macrophages, indicating a fundamental role of metal metabolism in shaping the immune response. 56 IL-4 elevation by Cd supports our previous study of Cd-increased airway reactivity.…”

“…56,57 Interestingly, it was shown that increase in Zn may promote pathogen persistence in macrophages, indicating a fundamental role of metal metabolism in shaping the immune response. 56 IL-4 elevation by Cd supports our previous study of Cd-increased airway reactivity. 25 IL-4 is known as a central cytokine in the development of inflammatory response in allergies and asthma.…”