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.
Highlights
The metal zinc is nowadays well established to be essential for a well-operating immune system
This review focuses on the role of zinc in regulating intracellular signaling pathways in innate as well as adaptive immune cells
AC: adenylate cyclase; cAMP: cyclic adenosine monophosphate; cyclic guanosine monophosphate (cGMP): cyclic guanine monophosphate; CRP: c-reactive protein; dendritic cells (DC): dendritic cell; IL: interleukin; IFN: interferon; IRAK: interleukin-1 receptor-associated kinase; lymphocyte protein tyrosine kinase (Lck): lymphocyte-specific protein tyrosine kinas; mitogen activated protein kinases (MAPK): mitogen-activated protein kinase; MAPK phosphatases (MKP): MAP-kinase phosphatase; MyD88: myeloid differentiation primary response gene 88; NET: neutrophil extracellular traps; NK: natural killer; PDE: phosphodiesterase; Phorbol 12-myristate 13-acetate (PMA): Phorbol-12-myristat-13-acetat; PTEN: phosphatase and tensin homolog deleted on chromosome 10; STAT: signal transducers and activators of transcription; TCR: T cell receptor; antigen-presenting cell (APC): Antigen presenting cell; Th: T helper; TNF: tumor necrosis factor; TRIF: Toll-interleukin-1 receptor (TIR) domain-containing adaptor-inducing interferon
Summary
The metal zinc is nowadays well established to be essential for a well-operating immune system. Zinc deficiency is very common, with estimated two billion people worldwide being affected, and is identified as a major contributor to the burden of disease in developing countries. It is the 5th leading life-threatening factor, especially in developing countries [22]. Uptake mechanisms are not fully understood yet, zinc transporters are mainly involved in zinc uptake or zinc efflux [25] In this regard, Zrt-like, Irt-like protein (ZIP) is highly important since it is expressed along the entire GI tract acting as a major processor of zinc uptake into enterocytes from the apical membrane [26]. We will focus on the importance of different types of zinc signals in innate as well as adaptive immunity, and highlight altered signaling pathways due to changed intracellular free zinc level
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