Zinc as a Gatekeeper of Immune Function

Inga Wessels, Martina Maywald, Lothar Rink, Inga Wessels, Martina Maywald, Lothar Rink

Abstract

After the discovery of zinc deficiency in the 1960s, it soon became clear that zinc is essential for the function of the immune system. Zinc ions are involved in regulating intracellular signaling pathways in innate and adaptive immune cells. Zinc homeostasis is largely controlled via the expression and action of zinc "importers" (ZIP 1-14), zinc "exporters" (ZnT 1-10), and zinc-binding proteins. Anti-inflammatory and anti-oxidant properties of zinc have long been documented, however, underlying mechanisms are still not entirely clear. Here, we report molecular mechanisms underlying the development of a pro-inflammatory phenotype during zinc deficiency. Furthermore, we describe links between altered zinc homeostasis and disease development. Consequently, the benefits of zinc supplementation for a malfunctioning immune system become clear. This article will focus on underlying mechanisms responsible for the regulation of cellular signaling by alterations in zinc homeostasis. Effects of fast zinc flux, intermediate "zinc waves", and late homeostatic zinc signals will be discriminated. Description of zinc homeostasis-related effects on the activation of key signaling molecules, as well as on epigenetic modifications, are included to emphasize the role of zinc as a gatekeeper of immune function.

Keywords: homeostatic zinc signal; immune function; signaling pathways; zinc deficiency; zinc flux; zinc wave.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Different Types of Zinc Signals: (A) Zinc Flux, as observed after receptor triggering (e.g., binding of lipopolysaccharide (LPS) to Toll like receptor (TLR)4), is generated within seconds. (B) A Zinc Wave, as is induced via immunoglobulin receptors and involving calcium flux, can be observed within a few minutes. (C) Homeostatic Zinc Signals, for example as observed after LPS stimulation of dendritic cells, take a few hours to be established and involve the expression of zinc transport and binding proteins. For explanations see the text. Abbreviations: ER: endoplasmic reticulum; ERK: extracellular signal-regulated kinase; MT: metallothionein; PLC: phospholipase c; R: receptor; Slp76, SH2 domain-containing leukocyte protein, 76 kD. Modified after [62,96,105].
Figure 2
Figure 2
Zinc in Toll like receptor 4-induced signaling. For explanation, see text. Abbreviations: A20: zinc finger protein; AP-1: Activator protein 1; ERK: extracellular Signal-regulated Kinase; IFN: interferon; IRAK: Interleukin-1 receptor-associated kinase; IκB: Inhibitor of NFκB; IKK: IκB kinase; IRF: interferon related factor; JAK: JNK janus kinase; JNK: c-Jun N-terminal Kinase; LPS: Lipopolysaccharide; MAPK: mitogen activated protein kinases MEK: MAPK/Erk kinase; MKK: MAPK kinase; MKP: MAPK phosphatase; MyD88: Myeloid differentiation primary response gene; NFkB: nuclear factor (NF)κB; PI3K: phosphatidyl-inositol-3-phosphate; RIP: receptor interacting protein; STAT: Signal transducers and activators of transcription; TAB: TAK-binding protein; TAK: TGF β-activated kinase; TBK: Tank-binding kinase 1; TIRAP: toll-interleukin 1 receptor (TIR) domain containing adaptor protein; TLR: Toll like receptor; TRAF: TNF receptor-associated factor; TRAM: TRIF-related adaptor molecule; TRIF: Toll-interleukin-1 receptor (TIR) domain-containing adaptor-inducing interferon. Altered from [97,176,178].
Figure 3
Figure 3
Zinc in TCR-induced signaling. For explanation, see text. Abbreviations: AP-1: Activator protein 1; CREB: cAMP response element-binding protein; Csk: C-terminal Src kinase; ER: endoplasmic reticulum; Lck: lymphocyte-specific protein tyrosine kinase; LAT: linker for activation of T cells; MAPK: mitogen activated protein kinases; MHC: major histocompatibility complex; MKP: MAP kinase phosphatase; NFAT: Nuclear factor of activated T cells; p50/p56: nuclear factor NF-kappa-B subunit p50/p65; PKA: protein kinase A; PKC: protein kinase C; Ras: Rat sarcoma; TCR: T cell receptor; ZAP: z-chain-associated protein kinase; Zip: Zrt-like, Irt-like proteins. Modified after [109,170].
Figure 4
Figure 4
Influence of zinc and zinc deficiency on various organ systems as well as on the immune system. Zinc deficiency is causally associated with multiple immunological dysfunctions that lead to the manifestation of various diseases indicated in this figure. For a detailed explanation see the text. Modified after [5]. ↑ = upregulted/enhanced.
Figure 5
Figure 5
Influence of zinc status on the overall immune function. Adequate zinc homeostasis is essential for a well-functioning immune system. Zinc deficiency as well as zinc excess lead to malfunction of the adaptive and innate immune system, eventually resulting in the development of numerous immune diseases.

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