Zinc Modulates Glutamine Metabolism in T Cells.

SCOPE: Zinc and glutamine are well known to be essential for the function and polarization of immune cells. TH 17 cells are more frequently induced during zinc deficiency and cover their energy requirement mainly through glutaminolysis. A dysregulation of TH 17 cells can contribute to the development of autoimmune diseases. Both inhibition of glutaminolysis and zinc supplementation suppress experimental autoimmune encephalomyelitis in mice. Therefore, the aim of this study is to investigate whether zinc modulates glutaminolysis in T cells. METHODS AND RESULTS: CD3/CD28 stimulation and mixed lymphocytes culture are used as in vitro models for T cell activation. Then, the glutaminolysis is investigated on mRNA, protein, and functional level. Zinc deficiency and glutaminase (GLS) inhibition decrease immune responses in vitro. Furthermore, extracellular zinc and glutamine levels both modulate glutaminolysis by changing the expression of glutamine transporters and key enzymes. Intriguingly, zinc directly interferes with the activity of GLS both in a cell free system and in the cytosol. CONCLUSION: Besides T cell subset differentiation, zinc also impacts on the cellular metabolism by inhibiting glutaminolysis. This suggests that zinc deficiency can contribute to the development of autoimmune diseases whereas zinc supplementation can support their therapy.

Zinc Levels Affect the Metabolic Switch of T Cells by Modulating Glucose Uptake and Insulin Receptor Signaling.

SCOPE: T cell activation requires a metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis to rapidly provide substrates for biosynthesis. An individual's zinc status plays an important role in balancing the activation of T cells and is required for a proper function of immune cells. Furthermore, zinc plays an important role during effector T cell polarization to T helper cell subsets or regulatory T cells, with effector T cells relying on glycolysis and regulatory T cells on oxidative phosphorylation. Therefore, the study aims to analyze if zinc also impacts on T cell activation on the level of intracellular metabolism. METHODS AND RESULTS: Mixed lymphocyte culture and anti-CD3/CD28 stimulation is used as in vitro models for T cell activation to investigate the effect of zinc supplementation and deprivation on metabolic switching. Promoted glucose uptake, insulin receptor expression, and signaling in both zinc conditions are observed, whereas key metabolic enzymes are stimulated mainly by zinc deprivation. Alterations in cytokine production suggest an immune-activating effect of zinc deprivation and a balancing effect of zinc supplementation. CONCLUSION: The results suggest a supportive effect of both zinc supplementation and deprivation on the metabolic switch during T cell activation, adding another level of immune regulation by zinc.

Dietary and Physiological Effects of Zinc on the Immune System.

Evidence for the importance of zinc for all immune cells and for mounting an efficient and balanced immune response to various environmental stressors has been accumulating in recent years. This article describes the role of zinc in fundamental biological processes and summarizes our current knowledge of zinc's effect on hematopoiesis, including differentiation into immune cell subtypes. In addition, the important role of zinc during activation and function of immune cells is detailed and associated with the specific immune responses to bacteria, parasites, and viruses. The association of zinc with autoimmune reactions and cancers as diseases with increased or decreased immune responses is also discussed. This article provides a broad overview of the manifold roles that zinc, or its deficiency, plays in physiology and during various diseases. Consequently, we discuss why zinc supplementation should be considered, especially for people at risk of deficiency.

Zinc supplementation ameliorates lung injury by reducing neutrophil recruitment and activity.

INTRODUCTION: Zinc is well known for its anti-inflammatory effects, including regulation of migration and activity of polymorphonuclear neutrophils (PMN). Zinc deficiency is associated with inflammatory diseases such as acute lung injury (ALI). As deregulated neutrophil recruitment and their hyper-activation are hallmarks of ALI, benefits of zinc supplementation on the development of lipopolysaccharides (LPS)-induced ALI were tested. METHODS: 64 C57Bl/6 mice, split into eight groups, were injected with 30 µg zinc 24 hours before exposure to aerosolised LPS for 4 hours. Zinc homoeostasis was characterised measuring serum and lung zinc concentrations as well as metallothionein-1 expression. Recruitment of neutrophils to alveolar, interstitial and intravascular space was assessed using flow cytometry. To determine the extent of lung damage, permeability and histological changes and the influx of protein into the bronchoalveolar lavage fluid were measured. Inflammatory status and PMN activity were evaluated via tumour necrosis factor α levels and formation of neutrophil extracellular traps. The effects of zinc supplementation prior to LPS stimulation on activation of primary human granulocytes and integrity of human lung cell monolayers were assessed as well. RESULTS: Injecting zinc 24 hours prior to LPS-induced ALI indeed significantly decreased the recruitment of neutrophils to the lungs and prevented their hyperactivity and thus lung damage was decreased. Results from in vitro investigations using human cells suggest the transferability of the finding to human disease, which remains to be tested in more detail. CONCLUSION: Zinc supplementation attenuated LPS-induced lung injury in a murine ALI model. Thus, the usage of zinc-based strategies should be considered to prevent detrimental consequences of respiratory infection and lung damage in risk groups.