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.

https://www.mdpi.com/2072-6643/9/12/1286/pdf/1

Zinc as a Gatekeeper of Immune Function

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.

https://www.mdpi.com/1422-0067/18/10/2222/pdf

Zinc Signals and Immunity.

Zinc has long been recognized as an essential trace element, playing roles in the growth and development of all living organisms. In recent decades, zinc homeostasis was also found to be important for the innate immune system, especially for maintaining the function of macrophages. It is now generally accepted that dysregulated zinc homeostasis in macrophages causes impaired phagocytosis and an abnormal inflammatory response. However, many questions remain with respect to the mechanisms that underlie these processes, particularly at the cellular and molecular levels. Here, we review our current understanding of the roles that zinc and zinc transporters play in regulating macrophage function.

/pdf/the-role-of-zinc-and-zinc-homeostasis-in-macrophage-function-5d0831kj15.pdf

The Role of Zinc and Zinc Homeostasis in Macrophage Function

Among the trace elements, zinc is one of the most used elements in biological systems. Zinc is found in the structure of more than 2700 enzymes, including hydrolases, transferases, oxyreductases, ligases, isomerases, and lyases. Not surprisingly, it is present in almost all body cells. Preserving the stability and integrity of biological membranes and ion channels, zinc is also an intracellular regulator and provides structural support to proteins during molecular interactions. It acts as a structural element in nucleic acids or other gene-regulating proteins. Metallothioneins, the low molecular weight protein family rich in cysteine groups, are involved significantly in numerous physiological and pathological processes including particularly oxidative stress. A critical role of metallothioneins (MT) is to bind zinc with high affinity and to serve as an intracellular zinc reservoir. By releasing free intracellular zinc when needed, MTs mediate the unique physiological roles of zinc. MT expression is induced by zinc elevation, and thus, zinc homeostasis is maintained. That MT mediates the effects of zinc, besides having strong radical scavenging effects, points to the critical part it plays in oxidative stress. The present review aims to give information on metallothioneins, which have critical importance in the metabolism and molecular pathways of zinc.

Zinc Metabolism and Metallothioneins.

A functional immune system is essential for healthy life. This is achieved by the coordinate activation and interaction of different immune cells. One should be aware that activation of the immune response is as important as its deactivation when the pathogens are cleared, as otherwise host tissue can be damaged up to life-threatening levels. Autoimmune diseases (AID) represent a phenomenon of immune cells attacking host cells and tissue. Five to eight percent of the world's population are currently affected by 80-100 AID. In recent years, the incidence has been constantly increasing, reaching alarmingly high numbers particularly for type 1 diabetes mellitus, Crohn's disease, rheumatoid arthritis, Sjogren's syndrome and multiple sclerosis. This indicates a higher societal burden of AID for the future. This article provides an overview of general concepts of triggers and underlying mechanisms leading to self-destruction. Lately, several original concepts of disease etiology were revised, and there is a variety of hypotheses on triggers, underlying mechanisms and preventive actions. This article concentrates on the importance of nutrition, especially zinc and vitamin D, for balancing the immune function. Homespun nutritional remedies seem to reenter today's therapeutic strategies. Current treatment approaches are largely symptomatic or suppress the immune system. However, recent studies reveal significant benefits of nutrition-related therapeutic approaches including prevention and treatment of established disease, which offer a cost-efficient and trigger-unspecific alternative addressing balancing rather than suppression of the immune system. Zinc and vitamin D are currently the best studied and most promising candidates for therapeutic intervention.

Micronutrients in autoimmune diseases: possible therapeutic benefits of zinc and vitamin D.

Mild zinc deficiency in humans negatively affects IL-2 production resulting in declined percentages of cytolytic T cells and decreased NK cell lytic activity, which enhances the susceptibility to infections and malignancies. T-cell activation is critically regulated by zinc and the normal physiological zinc level in T-cells slightly lies below the optimal concentration for T-cell functions. A further reduction in zinc level leads to T-cell dysfunction and autoreactivity, whereas high zinc concentrations (100 μM) were shown to inhibit interleukin-1 (IL-1)-induced IL-1 receptor kinase (IRAK) activation. In this study, we investigated the molecular mechanism by which zinc regulates the IL-1β-induced IL-2 expression in T-cells. Zinc supplementation to zinc-deficient T-cells increased intracellular zinc levels by altering the expression of zinc transporters, particularly Zip10 and Zip12. A zinc signal was observed in the murine T-cell line EL-4 6.1 after 1 h of stimulation with IL-1β, measured by specific zinc sensors FluoZin-3 and ZinPyr-1. This signal is required for the phosphorylation of MAPK p38 and NF-κB subunit p65, which triggers the transcription of IL-2 and strongly increases its production. These results indicate that short-term zinc supplementation to zinc-deficient T-cells leads to a fast rise in zinc levels which subsequently enhance cytokine production. In conclusion, low and excessive zinc levels might be equally problematic for zinc-deficient subjects, and stabilized zinc levels seem to be essential to avoid negative concentration-dependent zinc effects on T-cell activation.

Repletion of zinc in zinc-deficient cells strongly up-regulates IL-1β-induced IL-2 production in T-cells

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Repletion of zinc in zinc-deficient cells strongly up-regulates IL-1β-induced IL-2 production in T-cells