Zinc Signals and Immunity

Abstract

Zinc homeostasis is crucial for an adequate function of the immune system. Zinc deficiency as well as zinc excess result in severe disturbances in immune cell numbers and activities, which can result in increased susceptibility to infections and development of especially inflammatory diseases. This review focuses on the role of zinc in regulating intracellular signaling pathways in innate as well as adaptive immune cells. Main underlying molecular mechanisms and targets affected by altered zinc homeostasis, including kinases, caspases, phosphatases, and phosphodiesterases, will be highlighted in this article. In addition, the interplay of zinc homeostasis and the redox metabolism in affecting intracellular signaling will be emphasized. Key signaling pathways will be described in detail for the different cell types of the immune system. In this, effects of fast zinc flux, taking place within a few seconds to minutes will be distinguish from slower types of zinc signals, also designated as "zinc waves", and late homeostatic zinc signals regarding prolonged changes in intracellular zinc.

Keywords: homeostatic zinc signal; immune function; innate and adaptive immunity; signaling pathways; zinc deficiency; zinc flux; zinc wave.

Figure 1

Zinc in TLR4 triggered signaling, illustrating explanations in the text. Black arrow: activation, green arrow: activating function of zinc, red T bar: inhibiting function of zinc, black dotted arrow, translocation of the molecule to nucleus, grey dotted arrow: secretion of the molecule. Abbreviations: 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; MAPK: mitogen activated protein kinases MEK: MAPK/Erk kinase; MKK: MAPK kinase; MKP: MAPK phosphatase; MyD88: Myeloid differentiation primary response gene 88; NFκB: nuclear factor (NF) κB. PI3K: phosphatidyl-inositol-3-phosphate; STAT: signal transducers and activators of transcription; 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.

Figure 2

Complex impact of zinc on NFκB-centered signaling as illustration of signaling pathways described in the text. Red T bar: inhibitory function of zinc, green arrow: activating function of zinc, black T bar: inhibition, black arrow activation. Abbreviations: cGMP: cyclic guanine monophosphate; GC: guanine cyclase; GMP: guanine monophosphate; GTP: guanine triphosphate; ICAM: intercellular adhesion molecule; iNOS: inducible nitric oxide synthase; IKK: IκB kinase; IL: interleukin; MCP: monocyte chemoattractant protein; NIK: NFκB-inducing kinase; NFκB: nuclear factor (NF)κB; PDE: phosphodiesterase; PKA: protein kinase A; PPAR: Peroxisome proliferator-activated receptor; ROS: reactive oxygen species; STAT: Signal transducer and activator of transcription; TNF: tumor necrosis factor; VCAM: vascular cell adhesion molecule.

Figure 3

Influence of zinc signals on T cell signaling pathways. This figure presents an overview of T cell receptor (TCR)-, Interleukin-1 receptor (IL-1R)-, IL-2R-, IL-4R-, Transforming growth factor β1 receptor (TGF-β1R)-signaling in T cells, as well as zinc flux via zinc transporter ZIP6. Signaling pathways are described in detail in the text. Black arrow: activation, green arrow: activating function of zinc, red T bar: inhibiting function of zinc, black dotted arrow, translocation of the molecule to nucleus. Abbreviations: CREB: cyclic adenosine monophosphate response element-binding protein; Csk: c-src tyrosine kinase; Foxp3: forkhead-box-protein P3; IL: Interleukin; IRAK: interleukin-1 receptor-associated kinase; KLF-10: krüppel-like factor-10; Lck: lymphocyte-specific protein tyrosine kinase; MAPK: mitogen-activated protein kinase; MKP: MAP-kinase phosphatase; NFAT: nuclear factor of activated T cells; NFκB: nuclear factor kappa B; PKA: protein kinase A; PKC: protein kinase C; SIRT1: Sirtuin1; STAT: signal transducer and activator of transcription; TCR: T cell receptor; TGF-β1: transforming growth factor β1. ZAP: zeta-chain (TCR)-associated protein kinase.