Zinc signals and immune function

Abstract

For more than 50 years, it has been known that zinc deficiency compromises immune function. During this time, knowledge about the biochemistry of zinc has continued to grow, but only recent years have provided in-depth molecular insights into the multiple aspects of zinc as a regulator of immunity. A network based on ZnT and ZIP proteins for transport and metallothionein for storage tightly regulates zinc availability, and virtually all aspects of innate and adaptive immunity are affected by zinc. In vivo, zinc deficiency alters the number and function of neutrophil granulocytes, monocytes, natural killer (NK)-, T-, and B-cells. T cell functions and balance between the different subsets are particularly susceptible to changes in zinc status. This article focuses in particular on the main mechanisms by which zinc ions exert essential functions in the immune system. On the one hand, this includes tightly protein bound zinc ions serving catalytic or structural functions in a multitude of different proteins, in particular enzymes and transcription factors. On the other hand, increasing evidence arises for a regulatory role of free zinc ions in signal transduction, especially in cells of the immune system. Identification of several molecular targets, including phosphatases, phosphodiesterases, caspases, and kinases suggest that zinc ions are a second messenger regulating signal transduction in various kinds of immune cells.

Differential impact of zinc deficiency on phagocytosis, oxidative burst, and production of pro-inflammatory cytokines by human monocytes

“…19 In zinc deficient cells, Zip-transporters responsible for the movement of zinc into the cytosol are upregulated, while transporters of the ZnT-type needed for the reverse transport are downregulated. 8,[20][21][22][23][24] In our hands zinc is removed from the culture medium by CHELEX with over 90% efficiency. The remainder might still be sufficient for the cells to maintain free zinc, despite a state of general zinc deficiency.…”

“…29 NADPH oxidase activity is connected to the intracellular zinc status of the cell: it is inhibited both by zinc excess and zinc deficiency. 8 Furthermore, zinc deprivation of Histoplasma capsulatum has been shown to lead to increased susceptibility of the pathogen against ROS, whereas at the same time zinc accumulation improves ROS-tolerance of the host cell. 30,31 Oxidative burst is increased by zinc deficiency during macrophage differentiation.…”

“…Their release in response to stimulation using LPS can be enhanced in peripheral mononuclear blood cells (PBMC) by zinc supplementation, 4,7 and intracellular zinc signals are required for the production of pro-inflammatory cytokines in response to LPS. 8 Moreover, secretion of proinflammatory cytokines can also be directly induced by incubation with high extracellular Zn 2+ concentrations. 4 In contrast, high extracellular zinc concentrations have also been shown to inhibit LPS-induced monokine production.…”

Zinc in Infection and Inflammation

“…Recognition of major histocompatibility complex (MHC) class I by NK cells and the lytic activity of NK cells is influenced by zinc depletion. In terms of the adaptive immune response, zinc deficiency causes thymic atrophy and subsequent T-cell lymphopenia as well as reduction of premature and immature B cells, and consequently antibody production is also reduced [31]. The following section will delve deeper into how zinc influences immune cells and their mediators during inflammation and infection.…”

Differential expression of zinc transporters accompanies the differentiation of C2C12 myoblasts

“…Because the majority of Zn in mammalian cells is bound to metalloenzymes and stored in organelles and cellular vesicles, free zinc levels remain quite low [2,80–84]. Within the cell, about 50% of Zn is found in the cytoplasm and in vesicles, 30–40% in the nucleus, and about 10% in the cell membrane [85,86]. Moreover, 60% of the total systemic Zn is sequestered and used in skeletal muscle, making this organ the greatest reservoir of Zn in the body [87].…”