Zinc and immunity: An essential interrelation

doi:10.1016/j.abb.2016.03.022

Archives of Biochemistry and Biophysics

Volume 611, 1 December 2016, Pages 58-65

https://doi.org/10.1016/j.abb.2016.03.022 Get rights and content

Abstract

The significance of the essential trace element zinc for immune function has been known for several decades. Zinc deficiency affects immune cells, resulting in altered host defense, increased risk of inflammation, and even death. The micronutrient zinc is important for maintenance and development of immune cells of both the innate and adaptive immune system. A disrupted zinc homeostasis affects these cells, leading to impaired formation, activation, and maturation of lymphocytes, disturbed intercellular communication via cytokines, and weakened innate host defense via phagocytosis and oxidative burst. This review outlines the connection between zinc and immunity by giving a survey on the major roles of zinc in immune cell function, and their potential consequences in vivo.

Introduction

Zinc plays an important role in the immune system, affecting both innate and adaptive immune cells. This is highlighted by the effects of zinc deficiency, including thymic atrophy, lymphopenia, impaired cellular and antibody-mediated immune responses, and even death [1], [2]. Since the relationship between zinc deficiency and immune dysfunction was discovered about 50 years ago, it has been widely investigated [3]. The role of zinc in immune function, its effects on immune cells, and the underlying molecular mechanisms have been described [4], [5], including its importance as a signaling molecule [6], [7], [8]. Because zinc deficiency is closely linked to insufficient dietary intake or impaired resorption, especially people from developing countries, elderly, vegetarians/vegans, and patients with some chronic diseases, such as renal insufficiency and chronic diarrhea, are affected [9], [10], [11], [12]. Zinc supplementation can either restore or even improve immune function [13], [14], [15], [16] and has been used as a therapeutic treatment in chronic gastrointestinal disorders, renal diseases, and genetic predispositions, such as sickle cell anemia and the zinc malabsorption syndrome acrodermatitis enteropathica [11]. Physiological plasma zinc levels vary around 12–16 μM [17], [18], providing an important pool for immune cells [19]. In healthy individuals, substantial dietary zinc restriction significantly decreases plasma levels, whereas elevated zinc intake results in a plateau of plasma zinc, with most studies averaging around a value of 14 μM [20].

A disrupted zinc homeostasis causes impaired immune function, leading to compromised host defense and an increased risk of excessive inflammation. Deficiency and supplementation of this essential micronutrient are important factors influencing the immune system. Thus, the significance of zinc for selected innate and adaptive immune cells is discussed below.

Section snippets

Innate immune system

Upon recognition of characteristic molecular patterns of pathogens, the innate immune system initiates an immediate immune response, mainly maintained by neutrophil granulocytes, monocytes, and macrophages. They directly attack pathogens, complemented by natural killer cells, which recognize and kill virus-infected and tumor cells [21], [22]. Additionally, innate immune cells release various cytokines and chemokines, soluble proteins that are recognized by corresponding receptors on innate and

Adaptive immune system

The adaptive immune system is based on T- and B-lymphocytes, which express specific receptors on their surface to detect antigens - T-cell receptor (TCR) and B-cell receptor (BCR) [74], [75]. Antigens are defined as structures, which are recognized by these receptors or antibodies (= soluble BCR) and are mainly proteins and peptides, next to carbohydrates, lipids or any synthetic structure. Their specific recognition by these receptors results in a selective expansion in numbers and activation

Conclusion

The role of zinc in the immune system has been investigated in depth. As discussed above, altered zinc homeostasis critically influences innate and adaptive immunity, and therefore host defense and the immune response in general.

Zinc supplementation can reverse the negative effects of zinc deficiency, including impaired immune cell development, compromised T-cell-mediated immune response, decreased oxidative burst and many more. The potential benefits of zinc supplementation go from

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Nasopharyngeal Cancer (NPC) patients experience a deficiency immune system due to a systemic inflammatory response. Anorexia due to inflammation and dysphagia, as well as the effects of therapy such as chemotherapy and radiotherapy in NPC, causes a decreased intake of macronutrients and micronutrients, including zinc. Long-term zinc deficiency affects both non-specific and specific immune components (lymphocytes, monocytes, macrophages, neutrophils). However, research regarding zinc intake and lymphocyte counts is still rarely carried out, especially in NPC patients in Indonesia. The population of Indonesia has a different dietary intake pattern from the population of western countries. Therefore, researchers intend to examine zinc intake and lymphocyte counts in NPC patients at Dr. Kariadi Hospital in Semarang, Indonesia.
To determine the relationship between dietary zinc intake and Absolute Lymphocyte Counts (ALC) in NPC patients.
This study was a cross-sectional study involving NPC patients undergoing first to third cycles of chemotherapy and aged 18–59 years at Dr Kariadi Semarang in July 2020–October 2022. Patients with hypoalbuminemia, experienced metastases, had other comorbid diseases, and had undergone radiotherapy were excluded from this study. Dietary zinc intake was measured using the Food Frequency Questionnaire (FFQ) for the last 14 days and ALC was measured using a heme analyzer at Dr Kariadi Hospital Laboratory. Statistical analysis used the Pearson and Spearman correlation test to measure the strength of the correlation between dietary zinc intake and ALC, and a one sample T test to determine whether participants' zinc intake differed from the Recommended Dietary Allowance (RDA).
The sample of this research was 35 subjects [20 male subjects (57.1%) and 15 female subjects (42.1%)]. The average dietary zinc intake of NPC patients undergoing chemotherapy at Dr Kariadi Hospital was 5.18 ± 2.19 mg/day (5.83 ± 1.63 mg/day and 4.32 ± 2.58 mg/day for males and females, respectively). The results showed a positive correlation between dietary zinc intake and ALC in NPC patients (r = 0.41, p = 0.013; p < 0.05). ALC in NPC patients was influenced by zinc intake and protein intake (p < 0.05), but not energy intake, BMI, and age (p > 0.05). The zinc intake of men and women was significantly different compared to the RDA recommendation (p < 0.05).
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Zinc glycinate alleviates LPS-induced inflammation and intestinal barrier disruption in chicken embryos by regulating zinc homeostasis and TLR4/NF-κB pathway
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The effect of an immune challenge induced by a lipopolysaccharide (LPS) exposure on systemic zinc homeostasis and the modulation of zinc glycinate (Zn-Gly) was investigated using a chicken embryo model. 160 Arbor Acres broiler fertilized eggs were randomly divided into 4 groups: CON (control group, injected with saline), LPS (LPS group, injected with 32 µg of LPS saline solution), Zn-Gly (zinc glycinate group, injected with 80 µg of zinc glycinate saline solution) and Zn-Gly+LPS (zinc glycinate and LPS group, injected with the same content of zinc glycinate and LPS saline solution). Each treatment consisted of eight replicates of five eggs each. An in ovo feeding procedure was performed at 17.5 embryonic day and samples were collected after 12 hours. The results showed that Zn-Gly attenuated the effects of LPS challenge-induced upregulation of pro-inflammatory factor interleukin 1β (IL-1β) level (P =0.003). The LPS challenge mediated zinc transporter proteins and metallothionein (MT) to regulate systemic zinc homeostasis, with increased expression of the jejunum zinc export gene zinc transporter protein 1 (ZnT-1) and elevated expression of the import genes divalent metal transporter 1 (DMT1), Zrt- and Irt-like protein 3 (Zip3), Zip8 and Zip14 (P < 0.05). A similar trend could be observed for the zinc transporter genes in the liver, which for ZnT-1 mitigated by Zn-Gly supplementation (P =0.01). Liver MT gene expression was downregulated in response to the LPS challenge (P =0.004). These alterations caused by LPS resulted in decreased serum and liver zinc levels and increased small intestinal, muscle and tibial zinc levels. Zn-Gly reversed the elevated expression of the liver zinc finger protein A20 induced by the LPS challenge (P =0.025), while Zn-Gly reduced the gene expression of the pro-inflammatory factors IL-1β and IL-6, decreased toll-like receptor 4 (TLR4) and nuclear factor kappa-B p65 (NF-κB p65) (P < 0.05). Zn-Gly also alleviated the LPS-induced downregulation of the intestinal barrier gene Claudin-1. Thus, LPS exposure prompted the mobilization of zinc transporter proteins and MT to perform the remodeling of systemic zinc homeostasis, Zn-Gly participated in the regulation of zinc homeostasis and inhibited the production of pro-inflammatory factors through the TLR4/NF-κB pathway, attenuating the inflammatory response and intestinal barrier damage caused by an immune challenge.
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Data from electronic records of severe COVID-19 patients were correlated with serum zinc. Logistic regression investigated predictors and protectors of hypozincemia in men and women.
We assessed 188 medical records (men = 114, women = 74). In men, low zinc was correlated with hypertension (cc = 0.303, p < 0.001), diabetes (cc = 0.198, p = 0.031), hemoglobin (cc = −0.258, p = 0.005), and albumin (cc = −0.219, p = 0.027). Low lymphocyte count (cc = 0.315, p = 0.005), C-reactive protein (cc = −0.248, p = 0.037), and enteral nutrition (cc = 0.269, p = 0.016) were correlated with hypozincemia in women. Age correlated with low zinc in men (c = −0.304, p = 0.001) and women (cc = −0.298, p = 0.010). In men, hypertension (OR = 4.905, p = 0.005) and lymphopenia (OR = −0.999, p = 0.019) were low zinc predictors, while lung injury > 50% was a protective factor (OR = −0.280, p = 0.025). Lymphopenia (OR = −0.999, p = 0.005) and difficult weaning from mechanical ventilation (MV) (OR = 4.359, p = 0.036) were predictors of hypozincemia in women. Difficult weaning from MV (OR = 3.012, p = 0.003) and age (OR = 1.038, p = 0.002) were hypozincemia predictors regardless sex.
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Previous studies associate the disturbance of the Zinc (Zn) status with the severity of the disease and the inflammatory process in the critically ill patient. This decrease in Zn concentrations is an indicator of poor prognosis. Our aim was to evaluate Zn levels at admission and after four days, and to study if lower Zn levels at those days were related to a worse clinical outcome.
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129 subjects were invited to participate but only 100 subjects completed the survey. According to ROC curve [AUC= 0.63 (95% CI 0.60–0.66)], Zn < 79 μg/dL showed the best performance to detect a worse outcome (Sn=0.85; Sp=0.36). Patients with Zn < 79 μg/dL were older (70 vs 61 y; p = 0.002) with no differences by sex. Most patients presented with fever, dysthermic symptoms and cough, without differences between groups. Pre-existing comorbid conditions did not differ significantly between groups. Less obese subjects were found in the Zn < 79 μg/dL group (21.4 vs 43.3%, p = 0.025). In the univariate analysis, Zn < 79 μg/dL at hospital admission was related to a worse outcome (p = 0.044), but after adjusting for age, C-reactive protein, and obesity there was no difference, but a tendency towards a worse prognosis [OR 2.20 (0.63–7.70), p = 0.215]. Zn levels increased in both groups after 4 days (66.6 vs 73.1 μg/dL at admission, and 72.2 vs 80.5 μg/dL at 4th day), with ns. difference (p = 0.214).
Zn < 79 μg/dL at admission for a moderate to severe COVID-19 infection could be related to a worse outcome, although after adjustment for age, C-reactive protein levels and obesity, this Zn level threshold did not show statistically significant difference in the composite end point, but a tendency towards a worse prognosis. In addition, patients with the best clinical evolution showed higher serum Zn levels at 4th day after hospital admission than the patients with a worse prognosis.

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Zinc and immunity: An essential interrelation

Abstract

Introduction

Section snippets

Innate immune system

Adaptive immune system

Conclusion

J. Lab. Clin. Med.

J. Trace Elem. Med. Biol.

Immunol. Today

Trends Immunol.

Immunol. Today

Microbes Infect.

J. Nutr. Biochem.

Free Radic. Biol. Med.

Biochim. Biophys. Acta

Biochem. Biophys. Res. Commun.

Cytokine

Am. J. Clin. Nutr.

Exp. Gerontol.

Int. J. Biochem. Cell Biol.

Cell

J. Nutr.

Lancet

J. Nutr.

Mol. Immunol.

Cell Immunol.

Immunity

Toxicol. Lett.

Exp. Gerontol.

Serum thymulin in human zinc deficiency

J. Clin. Invest.

Chronic zinc deficiency in mice disrupted T cell lymphopoiesis and erythropoiesis while B Cell lymphopoiesis and myelopoiesis were maintained

J. Am. Coll. Nutr.

Syndrome of iron deficiency anemia, hepatosplenomegaly, hypogonadism, dwarfism and geophagia

Trans. Am. Clin. Climatol. Assoc.

Zinc-dependent suppression of TNF-alpha production is mediated by protein kinase A-induced inhibition of Raf-1, I kappa B kinase beta, and NF-kappa B

J. Immunol.

Zinc signals and immune function

Biofactors

Zinc signals are essential for lipopolysaccharide-induced signal transduction in monocytes

J. Immunol.

Zinc transporter SLC39A10/ZIP10 facilitates antiapoptotic signaling during early B-cell development

Proc. Natl. Acad. Sci. U. S. A.

Correlation between zinc status and immune function in the elderly

Biogerontology

Intestinal and placental zinc transport pathways

Proc. Nutr. Soc.

The dynamic link between the integrity of the immune system and zinc status

J. Nutr.

Zinc deficiency, malnutrition and the gastrointestinal tract

J. Nutr.

Effects of zinc supplementation in chronic haemodialysis patients

Nephrol. Dial. Transpl.

A Combination of high-dose vitamin C plus zinc for the common cold

J. Int. Med. Res.

Zinc enhances the number of regulatory T cells in allergen-stimulated cells from atopic subjects

Eur. J. Nutr.

Zinc regulates cytokine induction by superantigens and lipopolysaccharide

Immunology

Modulating the immune response by oral zinc supplementation: a single approach for multiple diseases

Arch. Immunol. Ther. Exp. Warsz.

Indicators of zinc status at the population level: a review of the evidence

Br. J. Nutr.

Differential impact of zinc deficiency on phagocytosis, oxidative burst, and production of pro-inflammatory cytokines by human monocytes

Metallomics

Innate or adaptive immunity? The example of natural killer cells

Science

Structure, regulation and function of NF-kappa B

Annu. Rev. Cell Biol.

Immunobiology and Hematology of Zinc

Zinc-reversible antimicrobial activity of recombinant calprotectin (migration inhibitory factor-related proteins 8 and 14)

J. Infect. Dis.

Polymorphonuclear leucocytes selectively produce anti-inflammatory interleukin-1 receptor antagonist and chemokines, but fail to produce pro-inflammatory mediators

Immunology

Neutrophil function: from mechanisms to disease

Annu. Rev. Immunol.

Zinc signals in neutrophil granulocytes are required for the formation of neutrophil extracellular traps

Innate Immun.

Effects of zinc on the reactive oxygen species generating capacity of human neutrophils and on the serum opsonic activity in vitro