Susceptibility to infectious diseases is determined by many factors, including pathogen virulence determinants, the genetic background of the host, and environmental conditions that can influence expression of the other two factors. Genetic analysis of laboratory mice has been an invaluable tool for the identification of host susceptibility determinants and pathogen-encoded virulence factors under controlled conditions. The discovery of a macrophage-specific metal transporter (Nramp1/ Slc11a1) that affects susceptibility to infection by several unrelated intracellular pathogens has focused attention on metal availability as a critical determinant of infection outcome. The involvement of many bacterial metal transport systems in virulence confirms the importance of divalent metals in the host-pathogen interaction. Here we summarize recent data on iron metabolism in macrophages, with a special emphasis on possible bacteriostatic and bactericidal consequences for intracellular pathogens. This review will include the role of biological chelators and transporters in normal macrophage physiology and antimicrobial defense.
Iron is an essential metal cofactor for many biochemical pathways in mammals. However, excess iron promotes the formation of cytotoxic oxygen derivatives so that systemic iron levels must be tightly regulated. In mammals (Fig. 1), dietary iron entering the duodenum is largely in the form of insoluble Fe3+ complexes that must be converted to soluble Fe2+ by the cytochrome b-like ferrireductase (Dcytb) (106) prior to capture and transport into enterocytes by Nramp2 (DMT1/Slc11a2), a pH-dependent metal transporter that functions by a proton cotransport mechanism at the apical brush border (23, 44, 65). Fe2+ is subsequently exported from enterocytes by another membrane transporter called ferroportin (Ireg1, MTP1, Slc40A1) into the portal bloodstream for systemic distribution via the transferrin (Tf) / Tf receptor (TfR) system (1, 40, 68, 107). This process appears to require the conversion of Fe2+ back to Fe3+ by the ferroxidase hephaestin, which functions to facilitate iron release from intestinal cells (28, 89, 150). Upon reaching its destination, Tf-Fe3+ binds to Tf receptors (TfR) at the cell surface and is internalized via clathrin-dependent endocytosis to reach recycling endosomes (68). From there, iron is released from Tf after acidification of the endosomal lumen by the vacuolar H+-ATPase and converted into Fe2+ by an as yet unidentified ferrireductase. Fe2+ is then transported across the membrane of acidified endosomes into the cytoplasm by Nramp2 to be stored in ferritin (Ft) or transported into the mitochondria for biosynthesis of new heme or iron-sulfur cluster-containing proteins. This process is particularly active in erythroid cells where the need for iron is substantial.
New iron is not only obtained from the diet, but also by recycling from erythrocytes within the reticuloendothelial system (68). Macrophages within the spleen, liver (Kupffer cells), and bone marrow appear critical for the latter process since they are responsible for phagocytosis and destruction of senescent red cells (68). The mechanism of iron recycling by macrophages including iron efflux from erythrocyte-containing phagosomes, iron release from macrophages, and entry into the Tf cycle remain poorly understood. The macrophage-specific iron transporter Nramp1 (see below) acts as a Fe2+ efflux pump at the phagosomal membrane and is therefore a candidate for involvement in this process (73). However, mice bearing loss-of-function Nramp1 mutations show no impairment of global iron homeostasis and are not anemic, suggesting that Nramp1 is not essential for this transport activity. Nramp2 is expressed in macrophages and has been reported to associate with phagosomes where it may efflux iron (71), but its functional role has not been demonstrated in this context. Ferroportin is expressed in macrophages and widely believed to play a critical role in iron recycling by these cells (1, 38, 40, 84, 85).
Because there is no known excretion system for iron in mammals, regulation of systemic iron levels occurs by controlling intestinal iron absorption and by expanding or mobilizing body stores (68). Iron is stored in Ft within hepatocytes and tissue macrophages, and the level of these stores is monitored and maintained by a "stores regulator" (68). When systemic iron demand in response to erythropoiesis exceeds what is available in storage pools, an "erythroid regulator" up-regulates intestinal iron uptake to compensate and replenish the stores. Of direct relevance to the host response to infection is the "inflammatory regulator." During infection or inflammation, marked retention of iron within tissue macrophages, along with reduced intestinal iron absorption, appears to restrict the amount of iron available to pathogens and thereby promote resistance to infection. Hepcidin, a small peptide produced by hepatocytes, has been shown to be a major regulator of these iron stores. In response to iron overload, hepatic expression of hepcidin is induced (124). Hepcidin-deficient (USF2−/−) mice develop tissue iron overload with iron depletion in splenic and liver macrophages, whereas hepcidin-overexpressing mice are anemic with marked iron accumulation in macrophages (114, 115). Hepcidin also appears to be an acute phase-response peptide induced directly by various inflammatory stimuli including bacterial lipopolysaccharide (LPS) (5, 99, 116, 135, 157). The mechanisms governing these regulatory networks are highly complex and, in general, beyond the scope of this review. For a detailed account of mammalian iron metabolism please refer to an excellent recent review (68).
Mature Nramp1 protein is found in the membrane fraction of macrophages as a 90- to 100-kDa phosphoglycoprotein (149). Sequence analysis indicates 12 putative transmembrane (TM) domains and a large glycosylated extracytoplasmic loop for which the location has recently been confirmed by topological studies (26, 48, 122). Susceptibility to bacterial/parasitic infection in Bcgs mouse strains is caused by a single Gly169 to Asp169 amino acid substitution in the predicted TM4 of Nramp1, which leads to a complete loss of the mature protein in macrophages (148, 149). This mutation appears to cause misfolding and retention of Nramp1 within the endoplasmic reticulum leading to its eventual degradation (155). Wild-type Nramp1 protein is localized to the membrane of Lamp-1-positive lysosomes or late-endosomes in primary macrophages or macrophage-derived cell lines (64), and in the tertiary, gelatinase-positive granules of neutrophils. During phagocytosis, Nramp1-containing lysosomal vesicles are incorporated into, and remain associated with, the membranes of phagosomes following uptake of latex particles (64) or live Salmonella, Leishmania, Mycobacterium, or Yersinia organisms (35, 57, 134).
Detailed analysis of the subcellular localization of Nramp2 in reticulocytes and transfected epithelial cells shows that the majority of Nramp2 (isoform II) is present in acidic TfR-positive recycling endosomes, where it acts to efflux Tf-delivered iron into the cytosol (24, 43, 62, 143). This endomembrane Nramp2 pool is in dynamic equilibrium with a smaller plasma membrane (PM) pool, and Nramp2 cycles between the two pools using phosphatidyl inositol-3-kinase-regulated exocytosis and Clathrin-dependent endocytic pathways (122, 143). In addition, Nramp2 has been shown to associate with Latex-bead- or red-blood-cell-containing phagosomes formed in J774 or RAW264.7 macrophages and with spermatozoids in testicle-derived phagocytes (Sertoli cell line TM4) (62, 71). Based on this colocalization it has been proposed that Nramp2 may participate in recycling of iron from senescent red blood cells or sperm cells after phagocytosis by specialized macrophages. This hypothesis is supported by studies showing that mk mice exhibit both microcytic anemia and reduced fertility due to impaired spermatogenesis (24, 44, 130). However, Nramp2 function in the phagosomal membrane remains to be fully characterized.
Although biochemical studies and sequence comparisons suggested that evolutionarily distant but related Nramp proteins share a common transport mechanism, Nramp1 at the phagosomal membrane, in particular, has been difficult to study, and therefore its mechanism of transport and substrate specificity have been controversial. Early studies reported increased Nramp1-dependent accumulation/binding of radioisotopic Fe2+ into isolated phagosomes containing either Latex beads or M. avium (87, 88, 165). This Fe2+ accumulation was abrogated by the addition of anti-Nramp1 antibodies suggesting that Nramp1 might transport cytoplasmic Fe2+ into phagosomes. A potential limitation of these studies was that phagosomal metal binding (whether Nramp1 dependent or independent) was not distinguished from transmembrane metal transport. A later study using Nramp1 mRNA injected into X. laevis oocytes found Zn2+-dependent inward currents to be induced over controls at an alkaline extracellular pH, which was suggestive of metal uptake against the experimental proton gradient (56). Based on additional pH-dependent transport studies using radioisotopic Zn2+, these authors concluded that Nramp1 might transport cytoplasmic metals into the phagosome by a proton/divalent-metal antiport mechanism. They proposed that increased phagosomal Fe2+ could stimulate oxygen radical production in situ via the Fenton reaction, resulting in increased bactericidal activity (56, 87, 88, 165). However, Nramp1-dependent phagosomal metal influx by an antiport mechanism would require a transport mechanism distinct from Nramp2, both with respect to the direction of transport and utilization of the transmembrane pH gradient.
Real-time microfluorescence imaging of zymosan particles chemically coupled with a metal-sensitive fluorophor (Fura-FF6) was used in another study to monitor divalent-metal flux across the membrane of individual phagosomes formed in live Nramp1+/+ or Nramp1−/− peritoneal macrophages (73). Following exposure of thapsigargin-permeabilized macrophages to high Mn2+ concentrations, Nramp1+/+ phagosomes accumulated less Mn2+ than did Nramp1−/− controls. Similarly, Nramp1+/+ phagosomes released more Mn2+ from preloaded Fura-FF6-zymosan particles than their Nramp1−/− counterparts. Dissipation of the phagosomal proton gradient by using concanamycin (a vacuolar H+-ATPase inhibitor) eliminated Nramp1-dependent Mn2+ transport, suggesting that Nramp1 functions in a pH-dependent fashion to efflux Mn2+ ions from acidified phagosomes down the proton gradient maintained by the vacuolar H+-ATPase. Independent biochemical studies support this model (7, 8).
To gain direct access to Nramp1for biochemical studies, we inserted an influenza hemagglutinin (HA) epitope into the TM7/8-loop of Nramp1 (Nramp1HA), which resulted in ectopic targeting of the recombinant protein to the PM of transfected CHO cells (48). Differential accessibility of the HA or N-terminal epitopes to extracellular antibodies in live cells revealed that the TM7/8 loop, which contains several predicted N-linked glycosylation sites (26), is extracellular and that the N terminus is cytoplasmic when Nramp1HA is expressed at the PM. Thus, the membrane organization of Nramp1HA at the PM is identical with the orientation established previously for Nramp2HA (122). The topology of the two proteins is also very similar to that of the E. coli MntH protein as determined by using PhoA reporter fusions (34). According to this topology, the TM7/8 loop of Nramp1 and Nramp2 is situated in the lumenal space of phagolysosomes or recycling endosomes, respectively.
These studies have convincingly established that Nramp1 and Nramp2 are functionally equivalent multispecific divalent-metal transporters both using a proton-coupled cotransport mechanism (48). The major physiological difference between Nramp1 and 2 appears to be their distinct subcellular sites of transport and tissue specificity. Nramp2 functions at the intestinal brush border to take up dietary iron and in other tissues transports Tf-delivered iron from the acidified lumen of recycling endosomes into the cytoplasm. The phagocyte-specific Nramp1 functions in an analogous fashion to remove divalent metals from the acidified phagosome. In both cases, luminal endomembrane acidification is generated by the vacuolar H+-ATPase that provides the proton gradient required for metal efflux (6, 67, 73). For a more complete discussion of Nramp protein biochemistry please refer to a recent review (102).
Ferroportin expression in the liver, spleen, and bone marrow cells appears to be restricted to macrophages (1, 40, 156). Mutant mice bearing a conditional deletion of the ferroportin gene in macrophages show retention of iron by hepatic Kupffer cells and splenic macrophages (41). Likewise, disruption of ferroportin expression by RNA interference results in macrophage iron accumulation and increased synthesis of ferritin, strongly suggesting that ferroportin participates in iron metabolism in macrophages (51). Therefore, ferroportin appears to act as the primary iron efflux system in macrophages. In LPS-stimulated or Leishmania donovani-infected mice, ferroportin expression in macrophages is down-regulated (156). In vitro studies have shown that IFN-γ and LPS treatment down-regulate ferroportin mRNA in monocytes (101) and macrophages (99) (F. Canonne-Hergaux and P. Gros, unpublished data). Hepcidin is induced by LPS in mouse spleens and splenic macrophage in vitro (99) and appears to mediate the LPS-induced down-regulation of ferroportin in the intestine (157) and in splenic macrophages (99), suggesting that inflammatory agents may regulate iron metabolism through modulation of ferroportin expression. Mutations in the human ferroportin gene cause an autosomal-dominant form of iron overload distinct from hemochromotosis, which is characterized by iron accumulation in the reticuloendothelial system (39, 111, 117, 123, 152).
Immunofluorescence experiments have detected ferroportin at the PM and within intracellular vesicles of macrophages (1, 37, 156). Ferroportin was originally localized to intracellular compartments of macrophages but not the PM, leading to the suggestion that cellular iron efflux by this protein may require redistribution of the protein to the PM in response to intracellular iron (85). This concept is supported by a recent study (37) showing that iron treatment or phagocytosis of red blood cells (erythrophagocytosis) resulted in strong localization of ferroportin to the PM of macrophage. Iron treatment caused an overall up-regulation of ferroportin protein levels, thus it remains unclear if PM localization of ferroportin is due to redistribution or increased expression. Treatment of macrophage with hepcidin was shown to cause a dramatic reduction in ferroportin protein levels and induce its rapid internalization and degradation (37, 84). Similarly, a ferroportin green fluorescent protein fusion (Fp-GFP) was shown to localize to the plasma membrane of HeLa or HEK293 cell lines in the absence of hepcidin (113). Direct binding of hepcidin to Fp-GFP at the cell surface caused the internalization and degradation of the protein with a concomitant decrease in iron efflux measured by changes in intracellular Ft levels. The authors of this study propose a homeostatic loop in which the levels of secreted hepcidin are regulated by iron, with subsequent control of ferroportin levels by modulation of both transcription and cell surface expression (113). In Kupffer cells, intracellular ferroportin vesicles are positive for hemosiderin (1), suggesting an additional role for ferroportin in intracellular iron trafficking.
It has long been established that mycobacteria survive within macrophages by preventing the maturation of phagosomes into fully bactericidal phagolysosomes (31, 32, 33, 129, 132, 137, 138) (Fig. 2). Permissive Nramp1−/− mycobacterial phagosomes exhibit impaired acidification due to a decreased number of vacuolar H+-ATPase pumps at the phagosomal membrane, as well as reduced acquisition of lysosomal markers, such as Lamp1 and the acid hydrolase Cathepsin D (129, 132, 137, 138). These phagosomes remain positive for sorting/early endosome markers, such as Rab5 and the TfR, and are accessible to exogenous Tf. Inhibition of maturation of Nramp1−/− mycobacterial phagosomes is an active process that only takes place with live, metabolically active mycobacteria. Nramp1 recruitment to the membrane of M. avium-containing phagosomes (in Nramp1+/+ cells) can prevent this mycobacterial-induced inhibition of maturation, resulting in increased bacterial damage, increased acidification, and enhanced fusion with lysosomes, with greater bacteriostasis than Nramp1−/− phagosomes (49, 67) (Fig. 2). In addition, Nramp1+/+ macrophages produce more nitric oxide (NO) in response to IFN-γ stimulation or mycobacterial infection than congenic Nramp1−/− controls, possibly contributing to the inhibition of bacterial growth (10, 11, 50).
One possible explanation for these findings is that the active inhibition of phagosome maturation by mycobacteria is a metal-dependent process that can be counteracted by Nramp1-mediated metal efflux from the phagosomal lumen. The ability of Nramp1 to antagonize mycobacterial-directed inhibition of phagosome maturation has been linked to iron levels (80). Rab5 is a cytosolic GTPase involved in regulation of endosome-phagosome fusion that may be utilized by mycobacteria to arrest phagosome maturation (32, 80). A dominant-negative Rab5 mutant was shown to force the maturation of M. avium-containing phagosomes into mature phagolysosomes in Nramp1−/− bone marrow macrophages, with a concomitant increase in bacteriostatic activity (80). Phagosomal maturation could be inhibited by preloading the macrophage with iron-citrate, suggesting that iron promotes the maturation block. Thus, Nramp1-induced depletion of phagosomal iron could impair the ability of mycobacteria to modulate phagolysosomal fusion.
As mentioned above, Nramp1 stimulates both acquisition of M6PR and accessibility of endosomes to SCVs. As with mycobacteria, this process has been linked to intracellular metals (72). Pretreatment of Nramp1−/− primary macrophages or the RAW264.7 macrophage cell line with the membrane-permeating iron chelators desferroxamine or salicylaldehyde isocotinoyl hydrazone restores the recruitment of M6PR and delivery of the fluid-phase marker rhodamine-dextran to SCVs at levels similar to those seen in macrophages expressing wild type Nramp1. These data suggest that Nramp1-mediated deprivation of iron and possibly of other divalent metals such as Mn2+ from the phagosomal space inhibits the ability of Salmonella to block phagosomal maturation. Thus, Nramp1-mediated metal efflux at the phagosomal membrane antagonizes the survival strategy of Salmonella.
In humans, global changes in systemic iron metabolism have been observed in response to acute or chronic inflammation (128). These changes include decreased serum Tf-Fe3+, decreased intestinal iron uptake, and marked retention of iron in macrophages. This syndrome has sometimes been referred to as the "anemia of chronic disease" (ACD) (154). ACD is thought to represent an adaptive response to limit the bioavailability of iron for pathogen growth during infection. Indeed, treatment of ACD by iron supplementation has been documented to have deleterious effects on the host, especially in immunocompromised patients (128, 154).
Of the macrophage iron transporters, only Nramp1 has been shown to act directly on pathogens as described above. However, like Nramp1, ferroportin and Nramp2 are modulated by immune stimuli in macrophages, suggesting a possible role in host defense through the establishment of ACD. In macrophages, Nramp2 is up-regulated in response to infection while expression of the TfR is simultaneously down-regulated (161). This would be expected to reduce the amount of Tf-Fe3+ available to intracellular pathogens within the endosomal system. Ferroportin down-regulation in response to infection/inflammation is thought to contribute to the establishment of ACD (154). This causes iron accumulation within macrophages and enterocytes, leading to systemic anemia and cellular iron restriction, including reduced circulating Tf-Fe3+. Macrophage iron accumulation is concomitant with increased Ft expression (154), which may act to sequester excess iron in the cytosolic compartment of macrophages during ACD, limiting its accessibility to pathogens contained within endomembrane compartments (i.e., mycobacterial phagolysosomes and SCV). Together, these metabolic changes in Tf, Ft, Nramp2, and ferroportin during infection may synergize with Nramp1 to limit bioavailability of iron to intracellular microbes and thus play a critical role at the interface of host and pathogen. Similar to ACD, inflammation and infection triggers hypozincemia, to which the zinc import protein Zip14 apparently contributes (100).
Lipocalins are a family of small proteins that bind hydrophobic ligands and are thought to serve as carriers for the delivery of small molecules to target cells (3). Of this protein family, Lipocalin-2 (Lcn2, siderocalin) has been identified as a component of the innate immune system involved in the acute phase response to bacterial infections (45, 81). In mice, Lcn2 mRNA and protein are induced in the liver and, to a lesser extent, in the spleen in response to E. coli infection or LPS treatment. Induction depends on toll-like receptor 4 (Tlr4) and peaks 24 h after infection along with a marked rise of Lcn2 protein in the serum (45). After intraperitoneal infection with E. coli, Lcn2−/− knockout mice suffer severe bacteremia, display increased bacterial load in spleen and liver, and have reduced survival compared with Lcn+/+ controls, demonstrating the antibacterial properties of Lcn2. Lcn2 has been shown to bind with high affinity to enterochelin-like siderophores produced by E. coli and Salmonella, as well as carboxymycobactins produced by Mycobacterium (45, 52, 69) (see elsewhere in EcoSal regarding iron-uptake systems). Lcn2 can directly inhibit enterochelin-dependent growth of cultured E. coli in a dose-dependent manner, an effect reversed by the addition of exogenous enterochelin (45). The antibacterial effect of Lcn2 can be reversed in mice by coinjection of ferrichrome, a siderophore to which Lcn2 does not bind, that can be utilized by E. coli as an alternative iron source. These observations suggest that Lcn2 contributes to bacterial resistance by interfering with enterochelin-like siderophore-dependent iron uptake by bacteria. Although Lcn2 itself acts only on certain types of siderophores, other Lcn2-like anti-siderophore molecules exist (46) or have been predicted to exist (69) and may collectively form a critical line of defense to prevent iron acquisition by invading pathogens.
Control of iron levels in the intraphagosomal environment constitutes a key battle fought between competing iron acquisition systems of both the host and microbial pathogen. The host transporter Nramp1 may compete directly with bacterial divalent-metal transport systems for the acquisition of divalent metals within the phagosomal space (47), a process further supported by the actions of Nramp2 and ferroportin at the systemic level. The ultimate outcome of these competing interactions influences the ability of pathogens to survive and replicate intracellularly. This seems particularly relevant to the Salmonella, Leishmania, and Mycobacterium spp., in which inactivating mutations in Nramp1 abrogate the natural resistance of macrophages to these pathogens.
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