Roles of Zinc Signaling in the Immune System

Abstract

Zinc (Zn) is an essential micronutrient for basic cell activities such as cell growth, differentiation, and survival. Zn deficiency depresses both innate and adaptive immune responses. However, the precise physiological mechanisms of the Zn-mediated regulation of the immune system have been largely unclear. Zn homeostasis is tightly controlled by the coordinated activity of Zn transporters and metallothioneins, which regulate the transport, distribution, and storage of Zn. There is growing evidence that Zn behaves like a signaling molecule, facilitating the transduction of a variety of signaling cascades in response to extracellular stimuli. In this review, we highlight the emerging functional roles of Zn and Zn transporters in immunity, focusing on how crosstalk between Zn and immune-related signaling guides the normal development and function of immune cells.

Figure 1

Zn transporters control Zn homeostasis. (1) Zn is ingested from the diet (or from breast milk in infants). (2) Zn is absorbed by intestinal Zn transporters and is released into the bloodstream. (3) Zn is taken up into peripheral cells by Zn transporters located on the plasma membrane. (4) Zn is distributed within the cell by intracellular Zn transporters. Each step is important for maintaining intracellular Zn levels. Disrupting Zn uptake results in ZnD and subsequent pathogenesis. ZIP (blue) and ZnT (red) transporters are indicated.

Figure 2

Subcellular localization of Zn transporters and metallothioneins (MTs). The localization of ZIP (blue) and ZnT (red) transporters is determined by the cell type, developmental process, and Zn status. ZIP transporters elevate the intracellular cytoplasmic Zn level by eliciting the influx of Zn from the extracellular space or from intracellular organelles. ZnT transporters reduce the intracellular cytoplasmic Zn level by exporting Zn from the cytosol to the extracellular space or into intracellular organelles or vesicles. MTs (green) contribute to Zn storage. Arrows indicate the predicted direction of Zn mobilization. ER: endoplasmic reticulum.

Figure 3

Zn uptake via LTCC and ZnT5 controls the FcεRI-mediated delayed allergic response by mast cells. Zn is indispensable for FcεRI-mediated mast-cell activation. Upon antigen sensitization, LTCC (blue) on the ER membrane acts as a Zn gatekeeper and can rapidly increase the intracellular-free Zn levels in the perinuclear region dependent on calcium and MAPK/ERK signaling (Zn wave). The released Zn then regulates the DNA-binding activity of NF-κB followed by cytokine production. Simultaneously, ZnT5 (red) on the Golgi membrane takes up Zn to regulate the translocation of PKC to the plasma membrane. The resultant NF-κB activation induces inflammatory cytokine production. Thus, these Zn gatekeepers and Zn transporter control mast-cell-mediated, delayed-type allergic reactions.

Figure 4

A decrease in intracellular-free Zn is critical for LPS-mediated CD4⁺ T-cell activation by DCs. LPS, a TLR4 ligand, induces DC activation, which initiates a maturation signal mediated by MyD88 and TRIF. TRIF-mediated signaling reduces the expression of ZIPs (blue) and increases that of ZnTs (red), resulting in a net decrease in the intracellular-free Zn level in DCs. This reduction of intracellular-free Zn is critical for the antigen presentation via MHC-II molecules and the subsequent activation of antigen-specific CD4⁺ T cells.

Figure 5

Zn uptake via ZIP6 and ZIP8 potentiates TCR signaling. Through the interaction of DCs and T cells, TCR activation rapidly increases cytoplasmic Zn concentrations, particularly at the subsynaptic compartment, in a manner dependent on ZIP6 (blue). The enhanced influx of Zn reduces SHP-1 recruitment to the TCR activation complex, thereby augmenting ZAP70 activation and leading to a sustained influx of calcium. On the other hand, TCR activation increases ZIP8 expression, which exports Zn out of the lysosome and into the cytoplasm (red). The resultant increase in cytoplasmic Zn inhibits CN, leading to increased CREB activation and the subsequent expression of IFN-γ. Thus, Zn facilitates TCR's functions in proliferation and IFN-γ production.

Figure 6

ZIP10's roles in B-cell development and function. In early B-cell development, a cytokine (1st signal) induces JAK-STAT activation (2nd signal), which is converted to an intracellular Zn signal (3rd signal) by ZIP10 upregulation. This system for converting intracellular signals promotes early B-cell survival by inhibiting caspase activation and/or by an unknown mechanism via molecule X (blue). In mature B cells, ZIP10-Zn signaling sets the threshold for the BCR signaling strength by regulating the CD45R PTPase activity (red). Thus, ZIP10 controls antibody-mediated immune responses.

Figure 7

Zn-signal axes in immune system. Each Zn-signal axis targets a specific molecule and controls a variety of cellular activities such as proliferation, differentiation, survival, migration, and function via a distinct signaling pathway to control immune homeostasis and functions. ZnD (red) impairs these Zn-signal axes and leads to disease if there is no redundant machinery.