Journal of Immunology Research

Journal of Immunology Research / 2018 / Article
Special Issue

Roles of Zinc and Zinc Mediators in Immunity

View this Special Issue

Review Article | Open Access

Volume 2018 |Article ID 6872621 | 11 pages | https://doi.org/10.1155/2018/6872621

The Role of Zinc and Zinc Homeostasis in Macrophage Function

Academic Editor: Ananda S. Prasad
Received01 Jun 2018
Revised31 Aug 2018
Accepted06 Nov 2018
Published06 Dec 2018

Abstract

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.

1. Introduction

A healthy human body usually contains 2–4 grams of zinc [1]. Approximately 60% of the body’s zinc is located in the skeletal muscle, 30% in the bone, 5% in the liver and the skin, and the remaining 2–3% in other tissues [2]. Internal zinc homeostasis is regulated by the cooperative activities of two metal transporter protein families. One family consists of ten solute-linked carrier 30 (SLC30 or ZnT) exporters, and the other family consists of fourteen solute-linked carrier 39 (SLC39, also known as Zrt- and Irt-like proteins, or ZIP) importers [3, 4]. The majority of labile zinc in the body is absorbed by intestinal epithelial cells via the metal transporter protein Slc39a4 [5], which is then transported into the plasma and utilized by nearly all cell types in the circulation. To maintain zinc homeostasis, excessive zinc is excreted through the kidneys [6] and the intestine [7] via Slc39a5.

Endogenous zinc is usually present in two forms in various organs and tissues. The majority of zinc is in a fixed pool in which zinc is tightly bound to metalloenzymes and zinc finger transcription factors; the remaining small amount of zinc is in a labile pool consisting of a variable amount of loosely bound zinc and free zinc ions [8]. In mammals, the plasma concentration of zinc ranges from 14 to 23 μmol/l under normal physiological conditions, and serum zinc accounts for only 0.1% of the body’s total zinc pool, 80% loosely bound by albumin and 20% bound by macroglobulin [9, 10]. Thus, sufficient daily intake of zinc is required to achieve steady-state levels. In order to meet the daily requirement, the World Health Organization recommends a daily zinc intake of 9.4–10 mg and 6.5–7.1 mg for men and women, respectively [11].

Zinc plays an important role in the immune system and affects both innate and adaptive immune cells. Many studies found that zinc deficiency can lead to a reduced immune response and increased susceptibility to infection [1216]. Moreover, endogenous zinc levels have been suggested to affect both the number and the function of various types of immune cells, including macrophages, neutrophils, dendritic cells, mast cells, T cells, and B cells [1724]. The underlying molecular mechanisms have been discussed in previous studies [25, 26], and the importance of zinc as a signaling molecule has been suggested [17, 27].

Macrophages play a key role in innate immunity by regulating numerous homeostatic, developmental, and host defense responses. Moreover, macrophages also participate in a wide range of other biological activities, including modulating endogenous levels of reactive oxygen species [28, 29], iron homeostasis [30], tissue repair, and metabolic processes [31]. Macrophages have three major functions—phagocytosis, antigen presentation, and immunomodulation—and are essential for maintaining normal immune status under a wide variety of pathophysiological conditions [32]. Many previous studies investigated the relationship between zinc and macrophages [3337]; however, some studies yielded contradictory results, and the underlying mechanisms are poorly understood. Here, we provide an overview of the latest studies regarding the role of zinc in macrophages.

2. Zinc Homeostasis in Macrophages

The regulation of zinc homeostasis is a complicated process. As a divalent cation, zinc is hydrophilic and does not readily pass lipid-based cell membranes via passive diffusion; thus, specialized transporters are required in order to facilitate its transport in and out of the cytoplasm. In macrophages and many other immune cells, SLC39 and SLC30 family members have distinct expression patterns and have various functions in response to infectious stimuli (Table 1).

(a)

Importer proteinsExpression in macrophagesExpression in other immune cellsInfection-related findings

Slc39a1Strong expression in the plasma membrane and cytoplasm in THP1-derived macrophages [44]Expressed in murine T cells [114]HIV-1 stimulated Slc39a1 expression in alveolar macrophages [115]
Slc39a2THP1 macrophages: weak expression mainly in nucleoli; TPEN significantly increases Slc39a2 expression
Alveolar macrophages: strong expression in the plasma membrane and cytoplasm [44]
No expression in human monocytes or in granulocytes [46]; moderated expression in murine DCs [116]Unknown
Slc39a3Strong expression in human monocytes [46]Expressed in human T cells and granulocytes [46]Unknown
Slc39a4Expressed in alveolar macrophages [117]Uniform expression in human monocytes and in granulocytes [46]Chronic alcohol exposure decreases Slc39a4 expression in alveolar macrophages [117]
Slc39a5UnknownNo expression in human monocytes or in granulocytes [46]Unknown
Slc39a6Strong expression in murine macrophages [22]Expressed in human DCs and T cells [20]LPS decreases the expression of Slc39a6 in human DCs; Slc39a6-silenced macrophages have increased TNFα expression following LPS stimulation [20]
Slc39a7Strong expression in murine macrophages [22], which can be inhibited by TPEN [45]Expressed in murine T cells [114]Unknown
Slc39a8Strong expression in both human and murine macrophagesStrong expression in human T cells [21]Both TNFα and LPS upregulate Slc39a8 expression in human macrophages, which increases zinc uptake and directly inhibits IKKβ [41] and IL-10 [42]
Slc39a9UnknownExpressed in murine T cells [114]Unknown
Slc39a10Strong expression in murine macrophagesExpressed in murine early B cells [23] and T cells [114]Slc39a10fl/fl; LysMCre+ mice have significantly decreased LPS-induced mortality due to increased macrophage apoptosis mediated by zinc-p53 signaling [22]
Slc39a11UnknownExpressed in murine T cells [114]Unknown
Slc39a12UnknownExpressed in murine T cells, expression is increased by zinc deficiency [114]Unknown
Slc39a13UnknownUnknownUnknown
Slc39a14Expressed in alveolar macrophages, expression is decreased by TPEN [44]Expressed in leukocytes; Slc39a14-knockout mice have delayed leukocytosis [118]LPS upregulates Slc39a14 expression and downregulates NF-κB in human macrophages [38]; Slc39a14-knockout mice have impaired zinc uptake and decreased plasma zinc and IL-6 levels following LPS stimulation [119]

(b)

Exporter proteinsExpression in macrophagesExpression in other immune cellsInfection-related findings

Slc30a1Expressed in alveolar macrophages, expression is decreased by TPEN [44]Expressed in murine DCs, expression is upregulated by LPS [18]M. tuberculosis infection upregulates Slc30a1 expression in human macrophages [111]
Slc30a2Weak expression in macrophages in the nulliparous mammary gland [47]; increased expression in murine macrophages during infection [39]No expression in human monocytes or granulocytes [46]Unknown
Slc30a3Expressed in alveolar macrophages, expression is decreased by TPEN [44]Expressed at low levels in human peripheral blood lymphocytes [48]Unknown
Slc30a4UnknownExpressed in murine DCs, expression is upregulated by LPS [18]; highly expressed in the human Molt-4 T cell line [48]GM-CSF upregulate Slc30a4 expression to transport zinc into Golgi [39]
Slc30a5Expressed in alveolar macrophages, expression is decreased by TPEN [44]Expressed in murine mast cells and required for the mast cell-mediated delayed-type allergic response [19]Unknown
Slc30a6Expressed in THP-1 monocytes, expression is upregulated by zinc deficiency [48]Expressed in murine DCs, expression is upregulated by LPS [18]Unknown
Slc30a7Expressed in THP-2 monocyte, expression is upregulated by zinc deficiency [48]Expressed in human B lymphocytes with the target molecule CD40 [120]GM-CSF upregulates Slc30a7 expression, leading to increased zinc transport into the Golgi apparatus [39]
Slc30a8UnknownExpressed in human peripheral blood lymphocytes [48]May function as an autoantigen targeted by disease-associated autoreactive T cells in humans [121]
Slc30a9Strong expression in murine macrophages [22]Expressed at low levels in human circulating blood lymphocytes [48]; expressed in murine T cells, expression is decreased by zinc deficiency [114]Unknown
Slc30a10UnknownUnknownUnknown

DCs: dendritic cells; GM-CSF: granulocyte-macrophage colony-stimulating factor; IL: interleukin; LPS: lipopolysaccharides; TPEN: N,N,N,N-tetrakis(2-pyridylmethyl)-ethylenediamine (a membrane-permeable zinc chelator).

Multiple SLC30/SLC39 members are expressed in macrophages. In untreated mouse macrophages, Slc39a1, Slc39a6, and Slc39a7 are the most robustly expressed genes in the Slc39a family, whereas the Slc30a5, Slc30a6, Slc30a7, and Slc30a9 genes are the most robustly expressed genes in the Slc30a family [22], suggesting that these transporters play an important role in macrophages under physiological conditions. However, under pathological conditions, other key transporters are expressed. For example, upon stimulation with lipopolysaccharides (LPS), which are found in the outer membrane of gram-negative bacteria, Slc39a10 expression is significantly downregulated, whereas Slc39a14 expression is strongly upregulated [22, 38]. Moreover, Slc39a2, Slc30a4, and Slc30a7 are significantly upregulated in GM-CSF-activated peritoneal and bone marrow-derived macrophages [39].

Several SLC30/39 members have been found to participate in the function of macrophages by mediating zinc homeostasis. Our recent study using macrophage-specific Slc39a10-knockout mice revealed that Slc39a10 plays an essential role in p53-dependent macrophage survival following LPS stimulation [22]. Interestingly, the trans-fatty acid elaidate was found to increase the expression of SLC39A10 and increase intracellular zinc levels in human macrophages [40], which also indicates the importance of Slc39a10 in zinc homeostasis in macrophages. In addition, several studies reported that SLC39A8 plays a role in inflammatory reactions [41, 42]. For example, LPS has been suggested to upregulate the expression of SLC39A8 in human macrophages, thereby increasing zinc uptake and reducing proinflammatory pathways by inhibiting Iκβ kinase (IKK) [41] and IL-10 [42]. Furthermore, SLC39A14 was also found to be upregulated in response to LPS stimulation in macrophages, thereby regulating cytokine production [38]. Moreover, systemic inflammation in mice resulted in the IL-6-dependent upregulation of the zinc importer Slc39a14, which mediates zinc uptake by hepatocytes in the liver [43]. Although previous studies summarized above suggest functions of Slc39a8, Slc39a10, and Slc39a14 in macrophages, potential roles of other SLC39/30 transporters in macrophages [22, 4448] remain to be explored.

Recently, a growing body of evidence supports the notion that zinc transporters transport not only zinc but also other divalent metals, including iron and manganese; for example, both SLC39A8 and SLC39A14 have been associated with iron and manganese transport [4955]. These findings raise the question of whether other SLC30/39 family members are involved in the development and functions of macrophage through mediating the homeostasis of other metals, such as iron or manganese.

In addition to the two zinc transporter families, intracellular zinc levels are also regulated by metallothioneins (MTs). Because of its toxicity, intracellular labile zinc is generally present in extremely low levels. Laurin et al. reported that adding zinc to the culture medium increased the rate of MT degradation and decreased the rate of MT synthesis and accretion in a chicken macrophage cell line [56].

Several groups reported that MTs play a role in macrophage function. MT-I/II-knockout mice developed more severe brain injury accompanied by increased numbers of T cells in the injury site and circulating leukocytes and the decreased number of alternatively activated macrophages in the circulation after 7-day treatment with brain cryolesion. These observations indicate that MT-I/II may have a neuroprotective role via modulation of the immune response [57]. Besides, Zbinden et al. measured increased numbers of macrophages in the ischemic hind limb of MT-deficient mice 21 days after ischemia was induced; moreover, CD11b+ macrophages isolated from MT-deficient mice were more invasive, which indicates that MT plays an important role in the recovery of collateral flow and angiogenesis, an effect mediated partly by macrophages [58]. In addition, in Salmonella typhimurium-infected human monocyte-derived macrophages, NOD2 mediates the induction of MT via NF-κB- and caspase-1-mediated IL-1β secretion. Moreover, the elevated MT level was found to upregulate intracellular zinc in a MTF-1-dependent manner. However, the underlying mechanism remains unclear [59]. Furthermore, during alternative activation of macrophages, IL-4 increases intracellular zinc dependence on metallothionein-3 (MT-3) and Slc30a4 and weakens the antimicrobial defense against intracellular pathogens [60]. In addition, matrix metallothionein 7 (MMP7) cleaves the precursor forms of α-defensin and β-defensin to produce their respective active forms [61], and MMP12 destroys the pathogen’s cell wall, leading to cell death [62]. In summary, a wide range of MTs are involved in maintaining macrophage function during the immune response.

3. Zinc and the Macrophage Cell Fate

Zinc homeostasis determines the cell fate of macrophages. In the innate immune system, monocytes migrate into the infected tissue and then differentiate into macrophages. Zinc supplementation increases the number of peritoneal macrophages in a T. cruzi infection model [63]. In addition, zinc-depleted monocytes have increased maturation, suggesting that low zinc status promotes their differentiation into macrophages [64]. High concentrations of zinc were found to decrease the viability of a human monocyte cell line and U-937 cells [65]. Moreover, another study confirmed that cell viability is significantly decreased in THP-1 monocytes/macrophages upon exposure to 100 μg/ml of ZnO (zinc oxide) particles. However, ZnO nanoparticles were found to induce the migration, adhesion, and cholesterol uptake of monocytes/macrophages, which may accelerate the formation of foam cells and lead to atherosclerosis [66]. Furthermore, a low-zinc environment can inhibit the differentiation of HL-60 cells into macrophages, and this inhibition can be partially prevented by the addition of exogenous zinc [67]. As in other cell types, both zinc deficiency and excessive zinc can induce apoptosis in macrophages. For example, using a genetic mouse model, we recently found that loss of Slc39a10 reduces zinc levels in macrophages, resulting in p53-dependent apoptosis, but not necroptosis, pyroptosis, ferroptosis, or autophagy [22]. On the other hand, zinc oxide nanoparticles have been shown to induce necrosis and apoptosis in RAW264.7 cells [6870]. These results suggest that altered zinc homeostasis induces distinct forms of cell death under different circumstances.

4. Zinc and Macrophage Function

Innate immunity provides a rapid, nonspecific defense against pathogens and is activated by pathogen-associated molecular patterns (PAMPs). During this process, conserved structures in pathogens are recognized by their respective receptors, including Toll-like receptors (TLRs), which then trigger phagocytosis, cytokine secretion, the killing of target cells, and/or antigen presentation [71]. Monocytes/macrophages mediate host defense via phagocytosis and oxidative burst. In addition, these cells can serve as antigen-presenting cells (APCs) and can secrete proinflammatory cytokines in order to regulate the immune response [72, 73]. Zinc plays a critical role in the immune function of macrophages, and this function has been implicated in a variety of pathological processes, including decreased connective tissue contraction [34].

4.1. Zinc and Phagocytosis by Macrophages

The level of intracellular zinc influences the phagocytosis capacity of macrophages, and zinc was recently linked to the antimicrobial response in macrophages [33]. In chronic obstructive pulmonary disease (COPD), impaired efferocytosis (i.e., clearance) of apoptotic epithelial cells by alveolar macrophages is mediated primarily by zinc restriction [44]. The transporters Slc39a1 and Slc39a2 respond differently to zinc deficiency and play important roles in macrophage-mediated efferocytosis [44]. On the other hand, zinc does not affect the phagocytic function of RAW264.7 cells [74] or bone marrow-derived macrophages [22] at nontoxic concentrations. Interestingly, a recent study by Mehta et al. found that alcohol abuse is associated with significant zinc deficiency in alveolar macrophages, which is accompanied by impaired immune function due to decreased phagocytosis-mediated bacterial clearance [75]. The authors also found that treating alveolar macrophages with zinc significantly improved their phagocytic capacity [75]. An earlier study by Wirth et al. found that zinc deficiency impairs the uptake and survival of protozoan parasites [76]. Zinc supplementation was also found to increase the phagocytosis of E. coli and Staphylococcus aureus by peritoneal macrophages in a mouse model of polymicrobial sepsis. Notably, Sheikh et al. reported that zinc deficiency decreases the phagocytic capacity of monocytes in children with enterotoxigenic E. coli-induced diarrhea, whereas treating patients with zinc (20 mg/day) or dietary zinc supplementation (10 mg/day) slightly improved the monocytes’ phagocytic capacity and significantly decreased their cellular oxidative burst capacity [77]. From a clinical perspective, these effects of zinc supplementation with respect to alleviating symptoms in zinc-deficient children are highly encouraging.

4.2. Zinc and Oxidative Burst in Macrophages

The relationship between zinc and the level of oxidative burst in macrophages after bacterial infection is controversial. Mayer et al. reduced zinc concentrations in peripheral blood mononuclear cells—which include monocytes—either by treating the cells with TPEN (N,N,N,N-tetrakis(2-pyridylmethyl)-ethylenediamine) or by removing zinc from the culture medium using the chelator Chelex 100. They found that the level of oxidative burst was significantly increased in zinc-deficient macrophages following infection with gram-positive S. aureus [73]. In addition, zinc is an inhibitor of NADPH, which is the electron donor for catalyzing the production of O2 [78]. On the other hand, Srinivas et al. found that macrophages obtained from E. coli-infected rats released significantly higher amounts of superoxide and that in vivo superoxide production was increased by zinc supplementation; nevertheless, they also found that zinc supplementation in vitro inhibited the production of superoxide by macrophages harvested from septic rats [79].

4.3. Zinc and Inflammatory Signaling in Macrophages

Zinc also plays essential roles in the signaling and inflammatory output of monocytes and macrophages, including many upstream activators of the Toll-like receptor (TLR) family, including mitogen-activated protein kinase (MAPK), protein kinase C (PKC), phosphodiesterases, and NF-κB [36, 37]. Indeed, the relationship between zinc and inflammatory signaling in monocytes/macrophages relies primarily on TLR signaling (e.g., via TLR4), which is activated by the phosphorylation of interleukin-1 receptor-associated kinase 1 (IRAK1). Zinc is known to be required for the degradation of IRAK1 in LPS-stimulated TLR activation both in vitro and in vivo; however, zinc is not required for the phosphorylation or ubiquitylation of IRAK1 in macrophages [80]. Nevertheless, zinc has been found to mediate the degradation of procaspase-1 and the NLRP3 (NLR family, pyrin domain containing 3), as well as to inhibit the production of IL-1β in macrophages following LPS stimulation or Salmonella infection. This effect may compromise the cell’s ability to clear microbial pathogens [45].

TLR4 signaling occurs via MyD88-dependent and TRIF-dependent pathways, and zinc has opposing effects on these two signaling pathways. Upon LPS stimulation, TLR4 first binds to the adapter proteins TIRAP and MyD88, which triggers the phosphorylation of MAP kinases and the early activation of NF-κB. Zinc signaling is required for preventing the dephosphorylation of the MAP kinases p38, MEK1/2, and ERK1/2, as well as the activation of NF-κB. Thus, zinc increases the release of inflammatory cytokines such as TNF-α, IL-1β, and IL-6 [81, 82]. Subsequently, the receptor complex is internalized and binds to TRAM and TRIF, inducing the delayed activation of NF-κB and the phosphorylation of IRF3. Phosphorylated IRF3 then translocated to the nucleus, where it induces the transcription of IFN-β [82, 83]. However, zinc can inhibit the phosphorylation of IRF3 and can prevent the secretion of IFN-β [82]. Moreover, zinc supplementation could downregulate inflammatory cytokines through upregulation of A20 to inhibit NF-κB activation [78, 84].

Zinc deficiency has diverse effects on inflammation. Zinc deficiency over the long term reduces the integrity of lysosomes, activates the NLRP3 inflammasome, and induces IL- secretion in macrophages [85], while in the short term, zinc depletion by TPEN inhibits inflammatory activation [86]. Moreover, without adequate zinc, an inflammatory response can also be elicited in cells, in part by causing the aberrant activation of immune cells and/or by altering promoter methylation [87]. In addition, a recent study found that zinc deficiency reduces the production of IL-6 and TNF-α in human monocytes [73]. Finally, zinc modulates LPS-induced inflammation in human macrophages by inducing SLC39A8 and by inhibiting C/EBPβ [42].

ZnO nanoparticles also affect the innate immune process. For example, ZnO nanoparticles have been shown to reduce bacterial skin infection by inducing oxidative stress and causing cell membrane breakdown in macrophages [88], as well as by reducing the innate immune response and attenuating the macrophage responses to bacterial infection [89]. In contrast, ZnO nanoparticles have been shown to induce a proinflammatory response in the RAW264.7 macrophage cell line [66, 90] and in peritoneal macrophages via TLR6-mediated MAPK signaling [91]. These seemingly contradictory results may be due—at least in part—to the different concentrations of nanoparticles and/or cell types used in the different studies.

Taken together, the evidence to date suggests that zinc regulates the function of macrophages in a variety of ways. For example, zinc deficiency induces the abnormal secretion of immune factors via distinct pathways in response to specific infections. In addition, oxidative stress caused by altered levels of zinc can lead to dysfunction of the innate immune system during acute inflammation.

According to a 2002 report by the World Health Organization, zinc deficiency ranks fifth among the most important health risk factors in developing countries and eleventh worldwide [92]; moreover, abnormal zinc homeostasis causes a variety of health problems with various levels of severity. In addition to the immune system, other organs and systems can also be affected by changes in zinc.

5.1. Immunological Diseases

The relationship between zinc and rheumatoid arthritis (RA) has been studied for more than three decades. RA is a chronic systemic inflammatory disease characterized by inflammation of the synovial membrane and the progressive destruction of the articular cartilage and bone [93]. Importantly, the number and activation level of macrophages in the inflamed synovial membrane/pannus are correlated with the severity of RA. A recent meta-analysis of 1444 RA cases and 1241 healthy controls revealed that patients with RA often have decreased serum zinc levels [94]. Correspondingly, the mean level of zinc was significantly lower in hair samples of RA patients compared with healthy individuals [95]. These clinical observations are supported by in vitro studies. For example, zinc deficiency increases the levels of TNF-α, IL-1β, and IL-8 in a monocyte-macrophage cell line [96]. In contrast, zinc supplementation inhibits the LPS-induced release of TNF-α and IL-1β in monocytes [97].

Chronic alcoholism can increase the risk of pneumonia and the development of acute respiratory distress syndrome (ARDS) [98]. As the resident bona fide phagocytic cell type in the lungs, alveolar macrophages play a central role in maintaining alveolar homeostasis, lung host defense, and immune regulation [99]. Several groups have studied the relationship between zinc levels and macrophage function in the alveolar space. For example, Mehta et al. found that alcohol-fed rats have a 5-fold decrease in lung bacterial clearance compared to control-fed rats and providing dietary zinc supplementation to the alcohol-fed rats restored bacterial clearance and mitigated oxidative stress in the alveolar space, which was reflected by the relative balance between the thiol redox pair cysteine and cystine and by the increased nuclear binding of both PU.1 and Nrf2 in alveolar macrophages obtained from alcohol-fed rats [90, 100]. Similarly, Konomi et al. found that during pregnancy, intracellular zinc levels and the expression levels of the zinc transporters Zip1, ZnT1, and ZnT4 are decreased in alveolar macrophages after ethanol ingestion compared to control rats that did not ingest alcohol. In addition, bacterial clearance capacity was decreased in ethanol-treated alveolar macrophages, and the addition of zinc reversed these effects in vitro [101]. Furthermore, pulmonary zinc deficiency may be one of the mechanisms by which HIV-1 infection impairs alveolar macrophage immune function and renders infected individuals susceptible to severe pulmonary infection [102].

5.2. Nonimmunological Diseases

Evidence suggested that chronic inflammation that originated in the liver or adipose tissue plays an important role in the pathogenesis of obesity-related metabolic dysfunction [103]. In obese mice, zinc deficiency may increase leptin production and stimulate macrophage infiltration into the adipose tissue, suggesting that zinc is important in metabolic and macrophage-mediated inflammatory dysregulation in obesity [104]. Based on its anti-inflammatory and antioxidant functions, zinc also plays a protective role in atherosclerosis [105]. However, zinc deficiency does not appear to affect the uptake of low-density lipoprotein (LDL) by macrophages in vitro [106]. Interestingly, another study found that ZnO nanoparticles can induce the migration and adhesion of monocytes to endothelial cells and accelerate the formation of foam cells [107].

5.3. Pathogen Infection

A sufficient amount of zinc is essential for the host’s defense against pathogenic organisms. For example, in both human monocyte-derived macrophages and mouse macrophages, increased intracellular zinc levels induced by the continuous stimulation of pattern recognition receptors (PRRs) can increase the clearance of bacteria via autophagy [59]. Moreover, treating mice with zinc and/or all-trans retinoic acid supplements helps protect against infection by the pathogen Listeria monocytogenes [108].

Interestingly, zinc is not only required by host cells but is also required for invading pathogens. According to the “nutritional immunity” theory, specific essential elements are sequestered from pathogens in order to restrict their growth [109, 110]. Zinc chelation was shown to restrict the growth of certain pathogens, for example, Histoplasma capsulatum [64]. A previous study found that zinc deprivation may be a defense mechanism utilized by the host’s macrophages [35]. Moreover, when stimulated with granulocyte macrophage-colony stimulating factor (GM-CSF), macrophages infected with Histoplasma capsulatum sequester zinc by inducing zinc binding to metallothionein (MT) proteins [39]. In addition, human macrophages attack intracellular Mycobacterium tuberculosis pathogens by inducing a “burst of labile zinc” and by increasing the expression of the zinc-binding proteins MT1, MT2, and ZnT1 [111], as well as possibly releasing zinc stored in zincosomes [112]. Macrophages can also use a “zinc trap” [113] to kill pathogens; this mechanism may be impaired when intracellular zinc is either too high or too low.

6. Conclusions and Future Perspectives

The vital role that the micronutrient zinc plays in both health and disease has been known for many years. Regular intake of zinc and the coordinated function of zinc transporters are essential for maintaining zinc homeostasis and for maintaining health. With respect to innate immunity, the various functions of macrophages, which include phagocytosis and the secretion of immune-mediating factors, can be impaired by zinc imbalance, thereby inducing or exacerbating various inflammatory and/or disease processes, as illustrated in Figure 1.

Despite extensive research, the molecular mechanisms by which zinc regulates the fate and function of macrophages remain poorly understood. Similarly, the function of zinc transporters is largely uninvestigated. In some cases, particularly when accompanied by a defect in a zinc transporter, oral zinc supplementation or restriction may not be sufficient for preventing diseases caused by cellular zinc imbalance; therefore, molecular approaches are needed in order to develop innovative new therapeutic approaches to correct the underlying defect. Given the development of powerful gene editing tools, the genetic manipulation of zinc transporters can be performed in various model systems, and research based on these models will likely shed light on the molecular function of these zinc transporters, as well as the mechanism of zinc in macrophages, ultimately guiding the treatment and prevention of zinc-related diseases.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

Hong Gao and Wei Dai contributed equally to this work.

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (31330036 and 31530034 to F. W.). We thank the members of the Wang and Min laboratories for helpful discussions.

References

  1. M. Maywald and L. Rink, “Zinc homeostasis and immunosenescence,” Journal of Trace Elements in Medicine and Biology, vol. 29, pp. 24–30, 2015. View at: Publisher Site | Google Scholar
  2. T. Kambe, T. Tsuji, A. Hashimoto, and N. Itsumura, “The physiological, biochemical, and molecular roles of zinc transporters in zinc homeostasis and metabolism,” Physiological Reviews, vol. 95, no. 3, pp. 749–784, 2015. View at: Publisher Site | Google Scholar
  3. L. Huang and S. Tepaamorndech, “The SLC30 family of zinc transporters - a review of current understanding of their biological and pathophysiological roles,” Molecular Aspects of Medicine, vol. 34, no. 2-3, pp. 548–560, 2013. View at: Publisher Site | Google Scholar
  4. J. Jeong and D. J. Eide, “The SLC39 family of zinc transporters,” Molecular Aspects of Medicine, vol. 34, no. 2-3, pp. 612–619, 2013. View at: Publisher Site | Google Scholar
  5. J. Geiser, K. J. T. Venken, R. C. de Lisle, and G. K. Andrews, “A mouse model of acrodermatitis enteropathica: loss of intestine zinc transporter ZIP4 (Slc39a4) disrupts the stem cell niche and intestine integrity,” PLoS Genetics, vol. 8, no. 6, article e1002766, 2012. View at: Publisher Site | Google Scholar
  6. Q. Qin, X. Wang, and B. Zhou, “Functional studies of Drosophila zinc transporters reveal the mechanism for dietary zinc absorption and regulation,” BMC Biology, vol. 11, no. 1, p. 101, 2013. View at: Publisher Site | Google Scholar
  7. J. Geiser, R. C. De Lisle, and G. K. Andrews, “The zinc transporter Zip5 (Slc39a5) regulates intestinal zinc excretion and protects the pancreas against zinc toxicity,” PLoS One, vol. 8, no. 11, article e82149, 2013. View at: Publisher Site | Google Scholar
  8. C. J. Frederickson, “Neurobiology of zinc and zinc-containing neurons,” International Review of Neurobiology, vol. 31, pp. 145–238, 1989. View at: Publisher Site | Google Scholar
  9. J. P. Barnett, C. A. Blindauer, O. Kassaar et al., “Allosteric modulation of zinc speciation by fatty acids,” Biochimica et Biophysica Acta (BBA) - General Subjects, vol. 1830, no. 12, pp. 5456–5464, 2013. View at: Publisher Site | Google Scholar
  10. J. G. Reyes, “Zinc transport in mammalian cells,” American Journal of Physiology, vol. 270, no. 2, pp. C401–C410, 1996. View at: Publisher Site | Google Scholar
  11. W. Maret and H. H. Sandstead, “Zinc requirements and the risks and benefits of zinc supplementation,” Journal of Trace Elements in Medicine and Biology, vol. 20, no. 1, pp. 3–18, 2006. View at: Publisher Site | Google Scholar
  12. A. H. Shankar and A. S. Prasad, “Zinc and immune function: the biological basis of altered resistance to infection,” American Journal of Clinical Nutrition, vol. 68, no. 2, pp. 447s–463s, 1998. View at: Publisher Site | Google Scholar
  13. H. Haase and L. Rink, “The immune system and the impact of zinc during aging,” Immunity & Ageing, vol. 6, no. 1, p. 9, 2009. View at: Publisher Site | Google Scholar
  14. P. J. Fraker and L. E. King, “Reprogramming of the immune system during zinc deficiency,” Annual Review of Nutrition, vol. 24, no. 1, pp. 277–298, 2004. View at: Publisher Site | Google Scholar
  15. L. Rink, “Zinc and the immune system,” The Proceedings of the Nutrition Society, vol. 59, no. 4, pp. 541–552, 2000. View at: Publisher Site | Google Scholar
  16. K. S. Vignesh, J. A. Landero Figueroa, A. Porollo, J. A. Caruso, and G. S. Deepe, “Zinc sequestration: arming phagocyte defense against fungal attack,” PLoS Pathogens, vol. 9, no. 12, article e1003815, 2013. View at: Publisher Site | Google Scholar
  17. H. Haase and L. Rink, “Zinc signals and immune function,” BioFactors, vol. 40, no. 1, pp. 27–40, 2014. View at: Publisher Site | Google Scholar
  18. H. Kitamura, H. Morikawa, H. Kamon et al., “Toll-like receptor-mediated regulation of zinc homeostasis influences dendritic cell function,” Nature Immunology, vol. 7, no. 9, pp. 971–977, 2006. View at: Publisher Site | Google Scholar
  19. K. Nishida, A. Hasegawa, S. Nakae et al., “Zinc transporter Znt5/Slc30a5 is required for the mast cell-mediated delayed-type allergic reaction but not the immediate-type reaction,” The Journal of Experimental Medicine, vol. 206, no. 6, pp. 1351–1364, 2009. View at: Publisher Site | Google Scholar
  20. M. Yu, W. W. Lee, D. Tomar et al., “Regulation of T cell receptor signaling by activation-induced zinc influx,” The Journal of Experimental Medicine, vol. 208, no. 4, pp. 775–785, 2011. View at: Publisher Site | Google Scholar
  21. T. B. Aydemir, J. P. Liuzzi, S. McClellan, and R. J. Cousins, “Zinc transporter ZIP8 (SLC39A8) and zinc influence IFN-γ expression in activated human T cells,” Journal of Leukocyte Biology, vol. 86, no. 2, pp. 337–348, 2009. View at: Publisher Site | Google Scholar
  22. H. Gao, L. Zhao, H. Wang et al., “Metal transporter Slc39a10 regulates susceptibility to inflammatory stimuli by controlling macrophage survival,” Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 49, pp. 12940–12945, 2017. View at: Publisher Site | Google Scholar
  23. T. Miyai, S. Hojyo, T. Ikawa et al., “Zinc transporter SLC39A10/ZIP10 facilitates antiapoptotic signaling during early B-cell development,” Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 32, pp. 11780–11785, 2014. View at: Publisher Site | Google Scholar
  24. S. Hojyo, T. Miyai, H. Fujishiro et al., “Zinc transporter SLC39A10/ZIP10 controls humoral immunity by modulating B-cell receptor signal strength,” Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 32, pp. 11786–11791, 2014. View at: Publisher Site | Google Scholar
  25. V. von Bulow, S. Dubben, G. Engelhardt et al., “Zinc-dependent suppression of TNF-α production is mediated by protein kinase a-induced inhibition of Raf-1, IκB Kinase β, and NF-κB,” Journal of Immunology, vol. 179, no. 6, pp. 4180–4186, 2007. View at: Publisher Site | Google Scholar
  26. A. S. Prasad, B. Bao, F. W. J. Beck, and F. H. Sarkar, “Zinc activates NF-κB in HUT-78 cells,” The Journal of Laboratory and Clinical Medicine, vol. 138, no. 4, pp. 250–256, 2001. View at: Publisher Site | Google Scholar
  27. H. Haase, J. L. Ober-Blobaum, G. Engelhardt et al., “Zinc signals are essential for lipopolysaccharide-induced signal transduction in monocytes,” Journal of Immunology, vol. 181, no. 9, pp. 6491–6502, 2008. View at: Publisher Site | Google Scholar
  28. Y. Zhang, S. Choksi, K. Chen, Y. Pobezinskaya, I. Linnoila, and Z. G. Liu, “ROS play a critical role in the differentiation of alternatively activated macrophages and the occurrence of tumor-associated macrophages,” Cell Research, vol. 23, no. 7, pp. 898–914, 2013. View at: Publisher Site | Google Scholar
  29. A. P. West, I. E. Brodsky, C. Rahner et al., “TLR signalling augments macrophage bactericidal activity through mitochondrial ROS,” Nature, vol. 472, no. 7344, pp. 476–480, 2011. View at: Publisher Site | Google Scholar
  30. M. Jung, C. Mertens, and B. Brune, “Macrophage iron homeostasis and polarization in the context of cancer,” Immunobiology, vol. 220, no. 2, pp. 295–304, 2015. View at: Publisher Site | Google Scholar
  31. F. Ginhoux and S. Jung, “Monocytes and macrophages: developmental pathways and tissue homeostasis,” Nature Reviews Immunology, vol. 14, no. 6, pp. 392–404, 2014. View at: Publisher Site | Google Scholar
  32. T. A. Wynn, A. Chawla, and J. W. Pollard, “Macrophage biology in development, homeostasis and disease,” Nature, vol. 496, no. 7446, pp. 445–455, 2013. View at: Publisher Site | Google Scholar
  33. S. L. Stafford, N. J. Bokil, M. E. S. Achard et al., “Metal ions in macrophage antimicrobial pathways: emerging roles for zinc and copper,” Bioscience Reports, vol. 33, no. 4, pp. 541–554, 2013. View at: Publisher Site | Google Scholar
  34. J. E. Nowak, K. Harmon, C. C. Caldwell, and H. R. Wong, “Prophylactic zinc supplementation reduces bacterial load and improves survival in a murine model of sepsis,” Pediatric Critical Care Medicine, vol. 13, no. 5, pp. e323–e329, 2012. View at: Publisher Site | Google Scholar
  35. M. S. Winters, Q. Chan, J. A. Caruso, and G. S. Deepe, Jr, “Metallomic analysis of macrophages infected with Histoplasma capsulatum reveals a fundamental role for zinc in host defenses,” The Journal of Infectious Diseases, vol. 202, no. 7, pp. 1136–1145, 2010. View at: Publisher Site | Google Scholar
  36. H. Haase and L. Rink, “Signal transduction in monocytes: the role of zinc ions,” Biometals, vol. 20, no. 3-4, pp. 579–585, 2007. View at: Publisher Site | Google Scholar
  37. H. Haase and L. Rink, “Functional significance of zinc-related signaling pathways in immune cells,” Annual Review of Nutrition, vol. 29, no. 1, pp. 133–152, 2009. View at: Publisher Site | Google Scholar
  38. A. Sayadi, A. T. Nguyen, F. A. Bard, and E. A. Bard-Chapeau, “Zip14 expression induced by lipopolysaccharides in macrophages attenuates inflammatory response,” Inflammation Research, vol. 62, no. 2, pp. 133–143, 2013. View at: Publisher Site | Google Scholar
  39. K. Subramanian Vignesh, J. A. Landero Figueroa, A. Porollo, J. A. Caruso, and G. S. Deepe Jr., “Granulocyte macrophage-colony stimulating factor induced Zn sequestration enhances macrophage superoxide and limits intracellular pathogen survival,” Immunity, vol. 39, no. 4, pp. 697–710, 2013. View at: Publisher Site | Google Scholar
  40. J. R. Zacherl, I. Tourkova, C. M. St. Croix et al., “Elaidate, an 18-carbon trans-monoenoic fatty acid, but not physiological fatty acids increases intracellular Zn(2+) in human macrophages,” Journal of Cellular Biochemistry, vol. 116, no. 4, pp. 524–532, 2015. View at: Publisher Site | Google Scholar
  41. M. J. Liu, S. Bao, M. Gálvez-Peralta et al., “ZIP8 regulates host defense through zinc-Mediated inhibition of NF-κB,” Cell Reports, vol. 3, no. 2, pp. 386–400, 2013. View at: Publisher Site | Google Scholar
  42. C. J. Pyle, S. Akhter, S. Bao, C. E. Dodd, L. S. Schlesinger, and D. L. Knoell, “Zinc modulates endotoxin-induced human macrophage inflammation through ZIP8 induction and C/EBPβ inhibition,” PLoS One, vol. 12, no. 1, article e0169531, 2017. View at: Publisher Site | Google Scholar
  43. J. P. Liuzzi, L. A. Lichten, S. Rivera et al., “Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 19, pp. 6843–6848, 2005. View at: Publisher Site | Google Scholar
  44. R. Hamon, C. C. Homan, H. B. Tran et al., “Zinc and zinc transporters in macrophages and their roles in efferocytosis in COPD,” PLoS One, vol. 9, no. 10, article e110056, 2014. View at: Publisher Site | Google Scholar
  45. M. Muroi and K. Tanamoto, “Zinc- and oxidative property-dependent degradation of pro-caspase-1 and NLRP3 by ziram in mouse macrophages,” Toxicology Letters, vol. 235, no. 3, pp. 199–205, 2015. View at: Publisher Site | Google Scholar
  46. T. B. Aydemir, R. K. Blanchard, and R. J. Cousins, “Zinc supplementation of young men alters metallothionein, zinc transporter, and cytokine gene expression in leukocyte populations,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 6, pp. 1699–1704, 2006. View at: Publisher Site | Google Scholar
  47. S. Lee, S. R. Hennigar, S. Alam, K. Nishida, and S. L. Kelleher, “Essential role for zinc transporter 2 (ZnT2)-mediated zinc transport in mammary gland development and function during lactation,” The Journal of Biological Chemistry, vol. 290, no. 21, pp. 13064–13078, 2015. View at: Publisher Site | Google Scholar
  48. S. Overbeck, P. Uciechowski, M. L. Ackland, D. Ford, and L. Rink, “Intracellular zinc homeostasis in leukocyte subsets is regulated by different expression of zinc exporters ZnT-1 to ZnT-9,” Journal of Leukocyte Biology, vol. 83, no. 2, pp. 368–380, 2008. View at: Publisher Site | Google Scholar
  49. K. Tuschl, E. Meyer, L. E. Valdivia et al., “Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia,” Nature Communications, vol. 7, article 11601, 2016. View at: Publisher Site | Google Scholar
  50. J. H. Park, M. Hogrebe, M. Grüneberg et al., “SLC39A8 deficiency: a disorder of manganese transport and glycosylation,” American Journal of Human Genetics, vol. 97, no. 6, pp. 894–903, 2015. View at: Publisher Site | Google Scholar
  51. K. M. Boycott, C. L. Beaulieu, K. D. Kernohan et al., “Autosomal-recessive intellectual disability with cerebellar atrophy syndrome caused by mutation of the manganese and zinc transporter gene SLC39A8,” American Journal of Human Genetics, vol. 97, no. 6, pp. 886–893, 2015. View at: Publisher Site | Google Scholar
  52. Y. Xin, H. Gao, J. Wang et al., “Manganese transporter Slc39a14 deficiency revealed its key role in maintaining manganese homeostasis in mice,” Cell Discovery, vol. 3, article 17025, 2017. View at: Publisher Site | Google Scholar
  53. X. Huang, L. Li, W. Junhao, J. Min, and F. Wang, “Functional discoveries and mechanistic studies of manganese transporters,” Chinese Bulletin of Life Sciences, vol. 30, pp. 603–614, 2018. View at: Publisher Site | Google Scholar
  54. C. Y. Wang, S. Jenkitkasemwong, S. Duarte et al., “ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading,” The Journal of Biological Chemistry, vol. 287, no. 41, pp. 34032–34043, 2012. View at: Publisher Site | Google Scholar
  55. S. Jenkitkasemwong, C. Y. Wang, R. Coffey et al., “SLC39A14 is required for the development of hepatocellular iron overload in murine models of hereditary hemochromatosis,” Cell Metabolism, vol. 22, no. 1, pp. 138–150, 2015. View at: Publisher Site | Google Scholar
  56. D. E. Laurin, D. M. Barnes, and K. C. Klasing, “Rates of metallothionein synthesis, degradation and accretion in a chicken macrophage cell line,” Proceedings of the Society for Experimental Biology and Medicine, vol. 194, no. 2, pp. 157–164, 1990. View at: Publisher Site | Google Scholar
  57. M. W. Pankhurst, W. Bennett, M. T. K. Kirkcaldie, A. K. West, and R. S. Chung, “Increased circulating leukocyte numbers and altered macrophage phenotype correlate with the altered immune response to brain injury in metallothionein (MT)-I/II null mutant mice,” Journal of Neuroinflammation, vol. 8, no. 1, p. 172, 2011. View at: Publisher Site | Google Scholar
  58. S. Zbinden, J. Wang, R. Adenika et al., “Metallothionein enhances angiogenesis and arteriogenesis by modulating smooth muscle cell and macrophage function,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 30, no. 3, pp. 477–482, 2010. View at: Publisher Site | Google Scholar
  59. A. Lahiri and C. Abraham, “Activation of pattern recognition receptors up-regulates metallothioneins, thereby increasing intracellular accumulation of zinc, autophagy, and bacterial clearance by macrophages,” Gastroenterology, vol. 147, no. 4, pp. 835–846, 2014. View at: Publisher Site | Google Scholar
  60. K. Subramanian Vignesh, J. A. Landero Figueroa, A. Porollo, S. Divanovic, J. A. Caruso, and G. S. Deepe Jr., “IL-4 induces metallothionein 3- and SLC30A4-dependent increase in intracellular Zn2+ that promotes pathogen persistence in macrophages,” Cell Reports, vol. 16, no. 12, pp. 3232–3246, 2016. View at: Publisher Site | Google Scholar
  61. C. L. Wilson, A. P. Schmidt, E. Pirila et al., “Differential processing of α- and β-defensin precursors by matrix metalloproteinase-7 (MMP-7),” Journal of Biological Chemistry, vol. 284, no. 13, pp. 8301–8311, 2009. View at: Publisher Site | Google Scholar
  62. A. M. G. Houghton, W. O. Hartzell, C. S. Robbins, F. X. Gomis-Rüth, and S. D. Shapiro, “Macrophage elastase kills bacteria within murine macrophages,” Nature, vol. 460, no. 7255, pp. 637–641, 2009. View at: Publisher Site | Google Scholar
  63. V. Brazão, L. C. Caetano, M. del Vecchio Filipin, M. Paula Alonso Toldo, L. N. Caetano, and J. C. do Prado Jr, “Zinc supplementation increases resistance to experimental infection by Trypanosoma cruzi,” Veterinary Parasitology, vol. 154, no. 1-2, pp. 32–37, 2008. View at: Publisher Site | Google Scholar
  64. S. Dubben, A. Honscheid, K. Winkler, L. Rink, and H. Haase, “Cellular zinc homeostasis is a regulator in monocyte differentiation of HL-60 cells by 1α, 25-dihydroxyvitamin D3,” Journal of Leukocyte Biology, vol. 87, no. 5, pp. 833–844, 2010. View at: Publisher Site | Google Scholar
  65. G. B. Vega-Robledo, A. Polo-Jimenez, M. E. Morales-Martinez, S. Rojas-Dotor, and G. Rico-Rosillo, “Effect of zinc upon human and murine cell viability and differentiation,” Biological Trace Element Research, vol. 120, no. 1-3, pp. 133–140, 2007. View at: Publisher Site | Google Scholar
  66. R. Roy, V. Parashar, L. K. S. Chauhan et al., “Mechanism of uptake of ZnO nanoparticles and inflammatory responses in macrophages require PI3K mediated MAPKs signaling,” Toxicology In Vitro, vol. 28, no. 3, pp. 457–467, 2014. View at: Publisher Site | Google Scholar
  67. D. Glesne, S. Vogt, J. Maser, D. Legnini, and E. Huberman, “Regulatory properties and cellular redistribution of zinc during macrophage differentiation of human leukemia cells,” Journal of Structural Biology, vol. 155, no. 1, pp. 2–11, 2006. View at: Publisher Site | Google Scholar
  68. V. Wilhelmi, U. Fischer, H. Weighardt et al., “Zinc oxide nanoparticles induce necrosis and apoptosis in macrophages in a p47phox- and Nrf2-independent manner,” PLoS One, vol. 8, no. 6, article e65704, 2013. View at: Publisher Site | Google Scholar
  69. V. Wilhelmi, U. Fischer, D. van Berlo, K. Schulze-Osthoff, R. P. F. Schins, and C. Albrecht, “Evaluation of apoptosis induced by nanoparticles and fine particles in RAW 264.7 macrophages: facts and artefacts,” Toxicology In Vitro, vol. 26, no. 2, pp. 323–334, 2012. View at: Publisher Site | Google Scholar
  70. R. Roy, S. K. Singh, L. K. S. Chauhan, M. Das, A. Tripathi, and P. D. Dwivedi, “Zinc oxide nanoparticles induce apoptosis by enhancement of autophagy via PI3K/Akt/mTOR inhibition,” Toxicology Letters, vol. 227, no. 1, pp. 29–40, 2014. View at: Publisher Site | Google Scholar
  71. A. Brocard and B. Dreno, “Innate immunity: a crucial target for zinc in the treatment of inflammatory dermatosis,” Journal of the European Academy of Dermatology and Venereology, vol. 25, no. 10, pp. 1146–1152, 2011. View at: Publisher Site | Google Scholar
  72. A. S. Prasad, “Zinc: role in immunity, oxidative stress and chronic inflammation,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 12, no. 6, pp. 646–652, 2009. View at: Publisher Site | Google Scholar
  73. L. S. Mayer, P. Uciechowski, S. Meyer, T. Schwerdtle, L. Rink, and H. Haase, “Differential impact of zinc deficiency on phagocytosis, oxidative burst, and production of pro-inflammatory cytokines by human monocytes,” Metallomics, vol. 6, no. 7, pp. 1288–1295, 2014. View at: Publisher Site | Google Scholar
  74. S. Triboulet, C. Aude-Garcia, L. Armand et al., “Analysis of cellular responses of macrophages to zinc ions and zinc oxide nanoparticles: a combined targeted and proteomic approach,” Nanoscale, vol. 6, no. 11, pp. 6102–6114, 2014. View at: Publisher Site | Google Scholar
  75. A. J. Mehta, S. M. Yeligar, L. Elon, L. A. Brown, and D. M. Guidot, “Alcoholism causes alveolar macrophage zinc deficiency and immune dysfunction,” American Journal of Respiratory and Critical Care Medicine, vol. 188, no. 6, pp. 716–723, 2013. View at: Publisher Site | Google Scholar
  76. J. J. Wirth, P. J. Fraker, and F. Kierszenbaum, “Zinc requirement for macrophage function: effect of zinc deficiency on uptake and killing of a protozoan parasite,” Immunology, vol. 68, no. 1, pp. 114–119, 1989. View at: Google Scholar
  77. A. Sheikh, S. Shamsuzzaman, S. M. Ahmad et al., “Zinc influences innate immune responses in children with enterotoxigenic Escherichia coli-induced diarrhea,” The Journal of Nutrition, vol. 140, no. 5, pp. 1049–1056, 2010. View at: Publisher Site | Google Scholar
  78. A. S. Prasad, B. Bao, F. W. J. Beck, O. Kucuk, and F. H. Sarkar, “Antioxidant effect of zinc in humans,” Free Radical Biology & Medicine, vol. 37, no. 8, pp. 1182–1190, 2004. View at: Publisher Site | Google Scholar
  79. U. Srinivas, B. Jeppsson, and J. H. Braconier, “Superoxide production of peritoneal macrophages in experimental gram-negative sepsis; influence of in vitro and in vivo supplements of zinc,” APMIS, vol. 97, no. 7-12, pp. 682–688, 1989. View at: Publisher Site | Google Scholar
  80. Y. Wan, M. J. Petris, and S. C. Peck, “Separation of zinc-dependent and zinc-independent events during early LPS-stimulated TLR4 signaling in macrophage cells,” FEBS Letters, vol. 588, no. 17, pp. 2928–2935, 2014. View at: Publisher Site | Google Scholar
  81. U. Siebenlist, G. Franzoso, and K. Brown, “Structure, regulation and function of NF-kappaB,” Annual Review of Cell Biology, vol. 10, no. 1, pp. 405–455, 1994. View at: Publisher Site | Google Scholar
  82. A. Brieger, L. Rink, and H. Haase, “Differential regulation of TLR-dependent MyD88 and TRIF signaling pathways by free zinc ions,” Journal of Immunology, vol. 191, no. 4, pp. 1808–1817, 2013. View at: Publisher Site | Google Scholar
  83. R. Ostuni, I. Zanoni, and F. Granucci, “Deciphering the complexity of toll-like receptor signaling,” Cellular and Molecular Life Sciences, vol. 67, no. 24, pp. 4109–4134, 2010. View at: Publisher Site | Google Scholar
  84. A. S. Prasad, B. Bao, F. W. J. Beck, and F. H. Sarkar, “Zinc-suppressed inflammatory cytokines by induction of A20-mediated inhibition of nuclear factor-κB,” Nutrition, vol. 27, no. 7-8, pp. 816–823, 2011. View at: Publisher Site | Google Scholar
  85. H. Summersgill, H. England, G. Lopez-Castejon et al., “Zinc depletion regulates the processing and secretion of IL-1β,” Cell Death & Disease, vol. 5, no. 1, article e1040, 2014. View at: Publisher Site | Google Scholar
  86. D. Brough, P. Pelegrin, and N. J. Rothwell, “Pannexin-1-dependent caspase-1 activation and secretion of IL-1β is regulated by zinc,” European Journal of Immunology, vol. 39, no. 2, pp. 352–358, 2009. View at: Publisher Site | Google Scholar
  87. C. P. Wong, N. A. Rinaldi, and E. Ho, “Zinc deficiency enhanced inflammatory response by increasing immune cell activation and inducing IL6 promoter demethylation,” Molecular Nutrition & Food Research, vol. 59, no. 5, pp. 991–999, 2015. View at: Publisher Site | Google Scholar
  88. R. Pati, R. K. Mehta, S. Mohanty et al., “Topical application of zinc oxide nanoparticles reduces bacterial skin infection in mice and exhibits antibacterial activity by inducing oxidative stress response and cell membrane disintegration in macrophages,” Nanomedicine, vol. 10, no. 6, pp. 1195–1208, 2014. View at: Publisher Site | Google Scholar
  89. C. D. Lin, Y. Y. Kou, C. Y. Liao et al., “Zinc oxide nanoparticles impair bacterial clearance by macrophages,” Nanomedicine (London, England), vol. 9, no. 9, pp. 1327–1339, 2014. View at: Publisher Site | Google Scholar
  90. M. Giovanni, J. Yue, L. Zhang, J. Xie, C. N. Ong, and D. T. Leong, “Pro-inflammatory responses of RAW264.7 macrophages when treated with ultralow concentrations of silver, titanium dioxide, and zinc oxide nanoparticles,” Journal of Hazardous Materials, vol. 297, pp. 146–152, 2015. View at: Publisher Site | Google Scholar
  91. R. Roy, S. K. Singh, M. Das, A. Tripathi, and P. D. Dwivedi, “Toll-like receptor 6 mediated inflammatory and functional responses of zinc oxide nanoparticles primed macrophages,” Immunology, vol. 142, no. 3, pp. 453–464, 2014. View at: Publisher Site | Google Scholar
  92. G. Chandel, K. Datta, and S. K. Datta, “Detection of genomic changes in transgenic Bt rice populations through genetic fingerprinting using amplified fragment length polymorphism (AFLP),” GM Crops, vol. 1, no. 5, pp. 327–336, 2010. View at: Publisher Site | Google Scholar
  93. E. Salgado and J. R. Maneiro, “New therapies for rheumatoid arthritis,” Medicina Clínica, vol. 143, no. 10, pp. 461–466, 2014. View at: Publisher Site | Google Scholar
  94. L. Xin, X. Yang, G. Cai et al., “Serum levels of copper and zinc in patients with rheumatoid arthritis: a meta-analysis,” Biological Trace Element Research, vol. 168, no. 1, pp. 1–10, 2015. View at: Publisher Site | Google Scholar
  95. A. Mierzecki, D. Strecker, and K. Radomska, “A pilot study on zinc levels in patients with rheumatoid arthritis,” Biological Trace Element Research, vol. 143, no. 2, pp. 854–862, 2011. View at: Publisher Site | Google Scholar
  96. B. Bao, A. S. Prasad, F. W. J. Beck, and M. Godmere, “Zinc modulates mRNA levels of cytokines,” American Journal of Physiology. Endocrinology and Metabolism, vol. 285, no. 5, pp. E1095–E1102, 2003. View at: Publisher Site | Google Scholar
  97. V. von Bulow, L. Rink, and H. Haase, “Zinc-mediated inhibition of cyclic nucleotide phosphodiesterase activity and expression suppresses TNF-α and IL-1β production in monocytes by elevation of guanosine 3,5-cyclic monophosphate,” Journal of Immunology, vol. 175, no. 7, pp. 4697–4705, 2005. View at: Publisher Site | Google Scholar
  98. A. T. Jacobs and L. J. Ignarro, “Cell density-enhanced expression of inducible nitric oxide synthase in murine macrophages mediated by interferon-beta,” Nitric Oxide, vol. 8, no. 4, pp. 222–230, 2003. View at: Publisher Site | Google Scholar
  99. W. J. Janssen, “Alveolar macrophage dysfunction and chronic alcohol use. Time to think about zinc,” American Journal of Respiratory and Critical Care Medicine, vol. 188, no. 6, pp. 635-636, 2013. View at: Publisher Site | Google Scholar
  100. A. J. Mehta, P. C. Joshi, X. Fan et al., “Zinc supplementation restores PU.1 and Nrf2 nuclear binding in alveolar macrophages and improves redox balance and bacterial clearance in the lungs of alcohol-fed rats,” Alcoholism, Clinical and Experimental Research, vol. 35, pp. 1519–1528, 2011. View at: Publisher Site | Google Scholar
  101. J. V. Konomi, F. L. Harris, X. D. Ping, T. W. Gauthier, and L. A. S. Brown, “Zinc insufficiency mediates ethanol-induced alveolar macrophage dysfunction in the pregnant female mouse,” Alcohol and Alcoholism, vol. 50, no. 1, pp. 30–38, 2015. View at: Publisher Site | Google Scholar
  102. P. C. Joshi, R. Raynor, X. Fan, and D. M. Guidot, “HIV-1-transgene expression in rats decreases alveolar macrophage zinc levels and phagocytosis,” American Journal of Respiratory Cell and Molecular Biology, vol. 39, no. 2, pp. 218–226, 2008. View at: Publisher Site | Google Scholar
  103. G. S. Hotamisligil, “Inflammation and metabolic disorders,” Nature, vol. 444, no. 7121, pp. 860–867, 2006. View at: Publisher Site | Google Scholar
  104. M. J. Liu, S. Bao, E. R. Bolin et al., “Zinc deficiency augments leptin production and exacerbates macrophage infiltration into adipose tissue in mice fed a high-fat diet,” The Journal of Nutrition, vol. 143, no. 7, pp. 1036–1045, 2013. View at: Publisher Site | Google Scholar
  105. B. Bao, A. S. Prasad, F. W. J. Beck et al., “Zinc decreases C-reactive protein, lipid peroxidation, and inflammatory cytokines in elderly subjects: a potential implication of zinc as an atheroprotective agent,” The American Journal of Clinical Nutrition, vol. 91, no. 6, pp. 1634–1641, 2010. View at: Publisher Site | Google Scholar
  106. A. Schmuck, F. Tricot, A. Hadjian, A. Favier, and A. M. Roussel, “Zinc deficiency does not enhance LDL uptake by P 388 D1 macrophages in vitro,” Biological Trace Element Research, vol. 47, no. 1-3, pp. 75–80, 1995. View at: Publisher Site | Google Scholar
  107. Y. Suzuki, S. Tada-Oikawa, G. Ichihara et al., “Zinc oxide nanoparticles induce migration and adhesion of monocytes to endothelial cells and accelerate foam cell formation,” Toxicology and Applied Pharmacology, vol. 278, no. 1, pp. 16–25, 2014. View at: Publisher Site | Google Scholar
  108. Y. Castillo, M. Tachibana, Y. Nakatsu, K. Watanabe, T. Shimizu, and M. Watarai, “Combination of zinc and all-trans retinoic acid promotes protection against Listeria monocytogenes infection,” PLoS One, vol. 10, no. 9, article e0137463, 2015. View at: Publisher Site | Google Scholar
  109. P. G. Sohnle, M. J. Hunter, B. Hahn, and W. J. Chazin, “Zinc-reversible antimicrobial activity of recombinant calprotectin (migration inhibitory factor-related proteins 8 and 14),” The Journal of Infectious Diseases, vol. 182, no. 4, pp. 1272–1275, 2000. View at: Publisher Site | Google Scholar
  110. W. Alker and H. Haase, “Zinc and Sepsis,” Nutrients, vol. 10, no. 8, 2018. View at: Publisher Site | Google Scholar
  111. H. Botella, P. Peyron, F. Levillain et al., “Mycobacterial p1-type ATPases mediate resistance to zinc poisoning in human macrophages,” Cell Host & Microbe, vol. 10, no. 3, pp. 248–259, 2011. View at: Publisher Site | Google Scholar
  112. G. Wellenreuther, M. Cianci, R. Tucoulou, W. Meyer-Klaucke, and H. Haase, “The ligand environment of zinc stored in vesicles,” Biochemical and Biophysical Research Communications, vol. 380, no. 1, pp. 198–203, 2009. View at: Publisher Site | Google Scholar
  113. K. Subramanian Vignesh and G. S. Deepe Jr., “Immunological orchestration of zinc homeostasis: the battle between host mechanisms and pathogen defenses,” Archives of Biochemistry and Biophysics, vol. 611, pp. 66–78, 2016. View at: Publisher Site | Google Scholar
  114. D. Daaboul, E. Rosenkranz, P. Uciechowski, and L. Rink, “Repletion of zinc in zinc-deficient cells strongly up-regulates IL-1β-induced IL-2 production in T-cells,” Metallomics, vol. 4, no. 10, pp. 1088–1097, 2012. View at: Publisher Site | Google Scholar
  115. P. C. Joshi and D. M. Guidot, “HIV-1 transgene expression in rats induces differential expression of tumor necrosis factor alpha and zinc transporters in the liver and the lung,” AIDS Research and Therapy, vol. 8, no. 1, p. 36, 2011. View at: Publisher Site | Google Scholar
  116. J. L. Peters, J. Dufner-Beattie, W. Xu et al., “Targeting of the mouse Slc39a2 (Zip2) gene reveals highly cell-specific patterns of expression, and unique functions in zinc, iron, and calcium homeostasis,” Genesis, vol. 45, no. 6, pp. 339–352, 2007. View at: Publisher Site | Google Scholar
  117. T. V. Curry-McCoy, D. M. Guidot, and P. C. Joshi, “Chronic alcohol ingestion in rats decreases Krüppel-like factor 4 expression and intracellular zinc in the lung,” Alcoholism, Clinical and Experimental Research, vol. 37, no. 3, pp. 361–371, 2013. View at: Publisher Site | Google Scholar
  118. I. Wessels and R. J. Cousins, “Zinc dyshomeostasis during polymicrobial sepsis in mice involves zinc transporter Zip14 and can be overcome by zinc supplementation,” American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 309, no. 9, pp. G768–G778, 2015. View at: Publisher Site | Google Scholar
  119. T. B. Aydemir, S.-M. Chang, G. J. Guthrie et al., “Zinc transporter ZIP14 functions in hepatic zinc, iron and glucose homeostasis during the innate immune response (endotoxemia),” PLoS One, vol. 7, no. 10, article e48679, 2012. View at: Publisher Site | Google Scholar
  120. S. Tepaamorndech, P. Oort, C. P. Kirschke, Y. Cai, and L. Huang, “ZNT7 binds to CD40 and influences CD154-triggered p38 MAPK activity in B lymphocytes-a possible regulatory mechanism for zinc in immune function,” FEBS Open Bio, vol. 7, no. 5, pp. 675–690, 2017. View at: Publisher Site | Google Scholar
  121. X. Xu, Y. Gu, L. Bian et al., “Characterization of immune response to novel HLA-A2-restricted epitopes from zinc transporter 8 in type 1 diabetes,” Vaccine, vol. 34, no. 6, pp. 854–862, 2016. View at: Publisher Site | Google Scholar

Copyright © 2018 Hong Gao et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


More related articles

2749 Views | 965 Downloads | 16 Citations
 PDF  Download Citation  Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

We are committed to sharing findings related to COVID-19 as quickly and safely as possible. Any author submitting a COVID-19 paper should notify us at help@hindawi.com to ensure their research is fast-tracked and made available on a preprint server as soon as possible. We will be providing unlimited waivers of publication charges for accepted articles related to COVID-19. Sign up here as a reviewer to help fast-track new submissions.