An Element of Life: Competition for Zinc in Host-Pathogen Interaction
2013; Cell Press; Volume: 39; Issue: 4 Linguagem: Inglês
10.1016/j.immuni.2013.09.009
ISSN1097-4180
Autores Tópico(s)Iron Metabolism and Disorders
ResumoZinc homeostasis plays a plethora of different roles in the immune response. In this issue of Immunity, Vignesh et al., 2013Vignesh K.A. Figueroa J.A.L. Porollo A. Caruso J.A. Deepe G.S. Immunity. 2013; 39 (this issue): 697-710Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar demonstrate that stimulation of macrophages with GM-CSF deprives intracellular Histoplasma capsulatum of zinc, improving pathogen clearance. Zinc homeostasis plays a plethora of different roles in the immune response. In this issue of Immunity, Vignesh et al., 2013Vignesh K.A. Figueroa J.A.L. Porollo A. Caruso J.A. Deepe G.S. Immunity. 2013; 39 (this issue): 697-710Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar demonstrate that stimulation of macrophages with GM-CSF deprives intracellular Histoplasma capsulatum of zinc, improving pathogen clearance. The essential trace element zinc (Zn) serves multiple functions in the immune system. It is a component of numerous enzymes and transcription factors (Maret, 2006Maret W. Antioxid. Redox Signal. 2006; 8: 1419-1441Crossref PubMed Scopus (241) Google Scholar) and acts as a second messenger in immune cells, e.g., in Toll-like receptor (TLR) signaling in macrophages (Haase and Rink, 2009Haase H. Rink L. Annu. Rev. Nutr. 2009; 29: 133-152Crossref PubMed Scopus (249) Google Scholar). Consequently, zinc homeostasis is tightly regulated by two families of transporter proteins. Fourteen solute carrier 39 (SLC39) proteins ZIP1 to ZIP14 move zinc ions into the cytosol. Depending on the subcellular localization of these transporters, the ions originate either from the extracellular environment or out of organelles. ZnT1 to ZnT10 from the SLC30 family carry zinc in the opposite direction (Lichten and Cousins, 2009Lichten L.A. Cousins R.J. Annu. Rev. Nutr. 2009; 29: 153-176Crossref PubMed Scopus (560) Google Scholar). Cellular zinc homeostasis is complemented by metal-binding proteins, most importantly the metallothioneins (MT) (Maret, 2006Maret W. Antioxid. Redox Signal. 2006; 8: 1419-1441Crossref PubMed Scopus (241) Google Scholar). During an immune response, the expression of all these proteins undergoes dynamic changes. For example, activation of dendritic cells with lipopolysaccharide (LPS) lowers expression of the zinc importer ZIP6. Reduced free intracellular zinc then leads to augmented maturation of the cells (Kitamura et al., 2006Kitamura H. Morikawa H. Kamon H. Iguchi M. Hojyo S. Fukada T. Yamashita S. Kaisho T. Akira S. Murakami M. Hirano T. Nat. Immunol. 2006; 7: 971-977Crossref PubMed Scopus (280) Google Scholar). In addition to zinc's roles in immune cells, a concept known as "nutritional immunity" has emerged. Here, the mammalian immune system utilizes the fact that several trace elements, including zinc, are essential for pathogens, but can also be toxic in excess (Hood and Skaar, 2012Hood M.I. Skaar E.P. Nat. Rev. Microbiol. 2012; 10: 525-537Crossref PubMed Scopus (978) Google Scholar). One mechanism of nutritional immunity is the starvation of pathogens from essential nutrients by their redistribution on the systemic level. To this end, inflammatory cytokines, such as interleukin-6 (IL-6), cause upregulation of ZIP14 on the plasma membrane of hepatocytes. Subsequently, MT-bound zinc accumulates in the liver, whereby plasma zinc is diminished (Lichten and Cousins, 2009Lichten L.A. Cousins R.J. Annu. Rev. Nutr. 2009; 29: 153-176Crossref PubMed Scopus (560) Google Scholar). In addition, some antimicrobial peptides from the S100 family act by chelating zinc. Secretion of calprotectin (a heterodimer of S100A8 and A9) by neutrophil granulocytes inhibits the growth of Staphylococcus aureus by sequestration of zinc and manganese (Corbin et al., 2008Corbin B.D. Seeley E.H. Raab A. Feldmann J. Miller M.R. Torres V.J. Anderson K.L. Dattilo B.M. Dunman P.M. Gerads R. et al.Science. 2008; 319: 962-965Crossref PubMed Scopus (655) Google Scholar). In a diametrically opposed strategy, macrophages have previously been shown to load toxic amounts of zinc into the phagosome, in order to poison intracellular Mycobacterium tuberculosis (Botella et al., 2012Botella H. Stadthagen G. Lugo-Villarino G. de Chastellier C. Neyrolles O. Trends Microbiol. 2012; 20: 106-112Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar). In this issue of Immunity, Vignesh and colleagues (Vignesh et al., 2013Vignesh K.A. Figueroa J.A.L. Porollo A. Caruso J.A. Deepe G.S. Immunity. 2013; 39 (this issue): 697-710Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar) show that removal of zinc from intraphagosomal Histoplasma capsulatum enhances clearance of this pathogen in macrophages (Figure 1). This leaves us with an intriguing question: how does the macrophage decide when to kill a pathogen by intoxication with zinc and when to utilize an opposing strategy based on deprivation? Innate immune cells can distinguish pathogens by different pattern-recognition receptors. This could directly affect each macrophage but also be communicated to others through the secretion of cytokines. As shown by Vignesh et al., granulocyte macrophage-colony stimulating factor (GM-CSF), which is a product of macrophages, strongly promotes zinc deprivation of H. capsulatum. GM-CSF is also produced by a variety of other cells, including T cells. Pattern-recognition receptors shape the ensuing adaptive immune response (Kawai and Akira, 2011Kawai T. Akira S. Immunity. 2011; 34: 637-650Abstract Full Text Full Text PDF PubMed Scopus (2588) Google Scholar), and the interaction with T-helper-cells could be another way to adjust macrophage zinc homeostasis. Infection with H. capsulatum led to several alterations in macrophage zinc homeostasis, which were significantly augmented by prior activation with GM-CSF (Vignesh et al., 2013Vignesh K.A. Figueroa J.A.L. Porollo A. Caruso J.A. Deepe G.S. Immunity. 2013; 39 (this issue): 697-710Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar). The authors presented a comprehensive study of changes in the expression of zinc homeostatic proteins (Figure 1). Zinc was removed from the phagosome, and thereby from H. capsulatum. The metal accumulated in the macrophage bound to cytosolic resident MTs, due to upregulation of MT1, MT2, and, surprisingly, in peritoneal macrophages also MT3. Expression of the latter is normally considered to be restricted to brain cells. Furthermore, upregulation of the zinc transporters ZnT4 and ZnT7 shifted the metal ions into the Golgi apparatus. At the same time, massive expression of ZIP2 caused the additional uptake of extracellular zinc into the macrophage, which was subsequently sequestered. All these events together resulted in important changes: less zinc was available for the pathogen in the phagosome, zinc accumulated in the Golgi and, bound to MT, in the cytosol, whereas free cytosolic zinc was reduced. Yet, one piece of the puzzle seems to be missing. Normally, pathogens develop effective defense mechanisms in an arms race for obtaining nutritional resources (Hood and Skaar, 2012Hood M.I. Skaar E.P. Nat. Rev. Microbiol. 2012; 10: 525-537Crossref PubMed Scopus (978) Google Scholar). For hepatocytes, upregulating MT in the cytosol is not sufficient to accumulate zinc from the periphery during the acute phase; it also requires the transporter ZIP14 (Lichten and Cousins, 2009Lichten L.A. Cousins R.J. Annu. Rev. Nutr. 2009; 29: 153-176Crossref PubMed Scopus (560) Google Scholar). Comparably, MT alone should not be sufficient to deprive H. capsulatum within macrophages of zinc, unless there is active transport out of the phagosome. Hence, the phagosomal membrane should contain a high-affinity zinc transporter in order to remove zinc. Transport into the cytosol points toward a member of the ZIP family. The authors did perform a complete analysis of gene expression for the ZIP proteins. Their findings indicated, besides a minor effect on ZIP14, only a strong regulation of ZIP2. However, silencing of Zip2 did not alter Zn deprivation of H. capsulatum. Nevertheless, this does not exclude ZIP-mediated phagosomal deprivation. Zinc transporters are not only controlled by their expression. Posttranscriptional regulation through serine phosphorylation has recently been described for ZIP7 (Taylor et al., 2012Taylor K.M. Hiscox S. Nicholson R.I. Hogstrand C. Kille P. Sci. Signal. 2012; 5: ra11PubMed Google Scholar). In a similar fashion, a transporter already present on the phagosomal membrane might be activated by phosphorylation to deplete the phagosome of zinc, which is then stored in the cytosol, bound to MT. At first glance, it seems surprising that macrophages upregulate ZIP2 in order to take up extracellular zinc, while the ultimate objective is to decrease phagosomal zinc content. They could conveniently dispose of zinc removed from H. capsulatum by storing it in the Golgi or exporting it through the plasma membrane by elevating the expression of the exporter ZnT1. Instead, the macrophages underwent the effort of synthesizing high amounts of MT for sequestering additional zinc. It is intriguing to speculate that this could be based on the well-documented antioxidant function of zinc and MT (Maret, 2006Maret W. Antioxid. Redox Signal. 2006; 8: 1419-1441Crossref PubMed Scopus (241) Google Scholar). The macrophage might be augmenting its own tolerance against reactive oxygen species (ROS) by accumulating zinc-saturated MT. At the same time, removal of zinc from the pathogen dismantled its antioxidant defense, rendering H. capsulatum more susceptible to ROS. In addition, the reduction in cytosolic-free zinc augmented the macrophages' oxidative burst by relieving inhibition of the phagosomal proton channel HV1, whose activity potentiates NADPH oxidase-mediated ROS production. Taken together, GM-CSF-mediated changes in macrophage zinc homeostasis seem to serve a triple function in host defense: (1) starving the pathogen of an essential nutrient, (2) augmenting ROS production, and (3) shifting the balance of redox tolerance in favor of the macrophage. As a next step, it will be important to elucidate which signals control the choice between killing by zinc deprivation or excess, whether this is specific for particular kinds of pathogens, and whether there might even be a connection to preferential susceptibility of different pathogens toward deprivation versus intoxication. During infection, there is fierce competition for trace elements on the systemic and also the intracellular level. The example of H. capsulatum and macrophages illustrates that this is particularly true for zinc, based on its nutritional importance, as well as its role in antioxidant defense; this makes zinc an essential element of life for pathogen and host alike. Granulocyte Macrophage-Colony Stimulating Factor Induced Zn Sequestration Enhances Macrophage Superoxide and Limits Intracellular Pathogen SurvivalSubramanian Vignesh et al.ImmunityOctober 17, 2013In BriefMacrophages possess numerous mechanisms to combat microbial invasion, including sequestration of essential nutrients, like zinc (Zn). The pleiotropic cytokine granulocyte macrophage-colony stimulating factor (GM-CSF) enhances antimicrobial defenses against intracellular pathogens such as Histoplasma capsulatum, but its mode of action remains elusive. We have found that GM-CSF-activated infected macrophages sequestered labile Zn by inducing binding to metallothioneins (MTs) in a STAT3 and STAT5 transcription-factor-dependent manner. Full-Text PDF Open Archive
Referência(s)