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EcoSal Plus

Domain 8:

Pathogenesis

Modulation of Iron Availability at the Host-Pathogen Interface in Phagocytic Cells

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  • Authors: John Forbes1, Steven Lam-Yuk-Tseung2, and Philippe Gros3
  • Editor: Michael S. Donnenberg4
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Biochemistry and Center for the Study of Host Resistance, McGill University, Montreal, Quebec, Canada H3G 1Y6; 2: Department of Biochemistry and Center for the Study of Host Resistance, McGill University, Montreal, Quebec, Canada H3G 1Y6; 3: Department of Biochemistry and Center for the Study of Host Resistance, McGill University, Montreal, Quebec, Canada H3G 1Y6; 4: University of Maryland, School of Medicine, Baltimore, MD
  • Received 07 December 2005 Accepted 03 March 2006 Published 28 June 2006
  • Address correspondence to Philippe Gros philippe.gros@mcgill.ca
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  • Abstract:

    This review summarizes recent data on iron metabolism in macrophages, with a special emphasis on possible bacteriostatic and bactericidal consequences for intracellular pathogens. It includes 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. The mechanism of iron recycling by macrophages including iron efflux from erythrocyte-containing phagosomes, iron release from macrophages, and entry into the transferrin (Tf) cycle remain poorly understood. Ferroportin expression in the liver, spleen, and bone marrow cells appears to be restricted to macrophages. Mutant mice bearing a conditional deletion of the ferroportin gene in macrophages show retention of iron by hepatic Kupffer cells and splenic macrophages. Hepcidin is induced by lipopolysaccharide (LPS) in mouse spleens and splenic macrophage in vitro and appears to mediate the LPS-induced down-regulation of ferroportin in the intestine and in splenic macrophages, suggesting that inflammatory agents may regulate iron metabolism through modulation of ferroportin expression. The host transporter Nramp1 may compete directly with bacterial divalent-metal transport systems for the acquisition of divalent metals within the phagosomal space. The ultimate outcome of these competing interactions influences the ability of pathogens to survive and replicate intracellularly. This seems particularly relevant to the , , and spp., in which inactivating mutations in Nramp1 abrogate the natural resistance of macrophages to these pathogens.

  • Citation: Forbes J, Lam-Yuk-Tseung S, Gros P. 2006. Modulation of Iron Availability at the Host-Pathogen Interface in Phagocytic Cells, EcoSal Plus 2006; doi:10.1128/ecosalplus.8.8.10

Key Concept Ranking

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ecosalplus.8.8.10.citations
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/content/journal/ecosalplus/10.1128/ecosalplus.8.8.10
2006-06-28
2017-05-29

Abstract:

This review summarizes recent data on iron metabolism in macrophages, with a special emphasis on possible bacteriostatic and bactericidal consequences for intracellular pathogens. It includes 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. The mechanism of iron recycling by macrophages including iron efflux from erythrocyte-containing phagosomes, iron release from macrophages, and entry into the transferrin (Tf) cycle remain poorly understood. Ferroportin expression in the liver, spleen, and bone marrow cells appears to be restricted to macrophages. Mutant mice bearing a conditional deletion of the ferroportin gene in macrophages show retention of iron by hepatic Kupffer cells and splenic macrophages. Hepcidin is induced by lipopolysaccharide (LPS) in mouse spleens and splenic macrophage in vitro and appears to mediate the LPS-induced down-regulation of ferroportin in the intestine and in splenic macrophages, suggesting that inflammatory agents may regulate iron metabolism through modulation of ferroportin expression. The host transporter Nramp1 may compete directly with bacterial divalent-metal transport systems for the acquisition of divalent metals within the phagosomal space. The ultimate outcome of these competing interactions influences the ability of pathogens to survive and replicate intracellularly. This seems particularly relevant to the , , and spp., in which inactivating mutations in Nramp1 abrogate the natural resistance of macrophages to these pathogens.

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Figures

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Figure 1

In mammals, dietary iron entering the duodenum is largely in the form of insoluble Fe complexes that must be converted to soluble Fe by the cytochrome -like ferrireductase (Dcytb) prior to capture and transport into enterocytes by Nramp2 (DMT1/Slc11a2), via a pH-dependent proton cotransport mechanism at the apical brush border. Fe is subsequently exported from enterocytes by ferroportin (Ireg1, MTP1, Slc40A1) into the portal bloodstream for systemic distribution via the transferrin (Tf)/Tf receptor (TfR) system. This process appears to require the conversion of Fe back to Fe by the ferroxidase hephaestin, which facilitates intestinal iron release. Upon reaching its destination (in this case a reticulocyte), Tf-Fe binds to TfRs at the cell surface and is internalized via clathrin-dependent endocytosis to reach recycling endosomes. From there, iron is released from Tf after acidification of the endosomal lumen by the vacuolar H-ATPase and converted into Fe by another ferrireductase. Fe 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 occurs in most cell types and is particularly active in erythroid cells, where the need for iron is substantial.

Citation: Forbes J, Lam-Yuk-Tseung S, Gros P. 2006. Modulation of Iron Availability at the Host-Pathogen Interface in Phagocytic Cells, EcoSal Plus 2006; doi:10.1128/ecosalplus.8.8.10
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Figure 2

Mycobacteria phagocytosed by macrophages are initially enclosed within a plasma membrane-derived phagosome. In macrophages, these phagosomes remain immature, displaying characteristics of early endosomes (EEs): positivity for TfR and retained access to Tf-bound iron. These immature phagosomes are permissive for bacterial replication. In macrophages, mycobacterial phagosomes fuse with Lamp1, H-ATPase, Cathepsin D, and Nramp1-positive late endosomes (LE)/lysosomes and mature into acidified phagolysosomes. Such phagosomes are nonpermissive for bacterial replication, and mycobacteria internalized under these conditions are destroyed. The mycobacterial inhibition of phagosome maturation is an active and metal-dependent process. Nramp1-mediated efflux of divalent metals, such as iron and manganese, at the phagosomal membrane antagonizes this process. Nramp1 has an analogous effect in modulating the fusogenic properties and antibacterial properties of SCV. Ferroportin is inducible by iron or copper and mediates the efflux of iron recycled by macrophages from phagocytosed red blood cells (erythrophagocytosis). During infection and inflammation ferroportin is repressed, contributing to the retention of iron within the cytosol during the establishment of “anemia of chronic disease” (ACD).

Citation: Forbes J, Lam-Yuk-Tseung S, Gros P. 2006. Modulation of Iron Availability at the Host-Pathogen Interface in Phagocytic Cells, EcoSal Plus 2006; doi:10.1128/ecosalplus.8.8.10
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