Expression and localization of hepcidin in macrophages: a role in host defense against tuberculosis

Sow, Fatoumata B.; Florence, William C.; Satoskar, Abhay R.; Schlesinger, Larry S.; Zwilling, Bruce S.; Lafuse, William P.

doi:10.1189/jlb.0407216

Cited by 205 publications

(179 citation statements)

References 50 publications

Supporting

Mentioning

169

Contrasting

Unclassified

Order By: Relevance

“…This physical interaction mediates the internalization and degradation of Fpn1, thus reducing cellular iron release [32]. Although a substantial upregulation of Hamp following infection with Mycobacterium avium or Mycobacterium tuberculosis and stimulation with IFN-c has recently been reported [44], we measured a small induction of Hamp transcripts in macrophages infected with S. typhimurium without any synergistic effect of IFN-c (Fig. 3).…”

Section: Discussionmentioning

confidence: 84%

Interferon‐γ limits the availability of iron for intramacrophage Salmonella typhimurium

et al. 2008

View full text Add to dashboard Cite

In stimulating effector functions of mononuclear phagocytes, IFN-c is of pivotal importance in host defense against intramacrophage pathogens including salmonellae. As the activity of IFN-c is modulated by iron and since a sufficient availability of iron is essential for the growth of pathogens, we investigated the regulatory effects of IFN-c on iron homeostasis and immune function in murine macrophages infected with Salmonella typhimurium. In Salmonella-infected phagocytes, IFN-c caused a significant reduction of iron uptake via transferrin receptor 1 and resulted in an increased iron efflux caused by an enhanced expression of the iron exporter ferroportin 1. Moreover, the expression of haem oxygenase 1 and of the siderophore-capturing antimicrobial peptide lipocalin 2 was markedly elevated following bacterial invasion, with IFN-c exerting a super-inducing effect. This observed regulatory impact of IFN-c reduced the intracellular iron pools within infected phagocytes, thus restricting the acquisition of iron by engulfed Salmonella typhimurium while concomitantly promoting NO and TNF-a production. Our data suggest that the modulation of crucial pathways of macrophage iron metabolism in response to IFN-c concordantly aims at withdrawing iron from intracellular Salmonella and at strengthening macrophage immune response functions. These regulations are thus consistent with the principles of nutritional immunity. IntroductionHost defense against intracellular microbes such as salmonellae or mycobacteria strongly depends on cell-mediated immunity, a major component of which is characterized by interactions between Th1 cells and macrophages [1]. By secreting Th1 cytokines, particularly IFN-c, antigen-specific Th1 cells activate a plethora of microbicidal mechanisms in infected macrophages. Specifically, in mononuclear phagocytes infected with Salmonella enterica serovar typhimurium (S. typhimurium), IFN-c promotes the internalization of bacteria and stimulates their elimination by various mechanisms including reactive oxygen and nitrogen species (ROS and RNS), generated via NADPH phagocyte oxidase and iNOS, respectively [2][3][4][5]. In Salmonella-infected mice, treatment with recombinant IFN-c increases host survival and decreases bacterial numbers in liver and spleen [6]. Conversely, neutralization of murine IFN-c functions with specific antibodies results in reduced host survival and increased bacterial counts [7]. Eur. J. Immunol. 2008. 38: 1923-1936 Immunity to infection In humans, the central importance of IFN-c for immune response against salmonellae is highlighted by the fact that patients with genetic defects in the IL-12-induced production of IFN-c or in the IFN-c receptor 1 selectively suffer from infections with salmonellae and otherwise weakly pathogenic mycobacteria since their phagocytes fail to eliminate these microbes [8,9]. Iron serves as an essential nutrient for nearly all pathogenic microorganisms, and the expression of iron acquisition systems by infectious agents is associated with their virule...

show abstract

Section: Discussionmentioning

confidence: 84%

Interferon‐γ limits the availability of iron for intramacrophage Salmonella typhimurium

et al. 2008

View full text Add to dashboard Cite

show abstract

“…36 Expression of hepcidin in cultured macrophages was also reported following infection with Mycobacterium avium and Mycobacterium tuberculosis. 37 Further, infection of macrophages with P aeruginosa resulted in a decrease in Fpn mRNA. We have not observed changes in Fpn levels in macrophages infected with C psittaci or L pneumophila.…”

Section: Org Frommentioning

confidence: 99%

Iron depletion limits intracellular bacterial growth in macrophages

Paradkar

Domenico

Durchfort

et al. 2008

Blood

189

166

View full text Add to dashboard Cite

Many intracellular pathogens infect macrophages and these pathogens require iron for growth. Here we demonstrate in vitro that the intracellular growth of Chlamydia psittaci, trachomatis, and Legionella pneumophila is regulated by the levels of intracellular iron. Macrophages that express cell surface ferroportin, the only known cellular iron exporter, limit the intracellular growth of these bacteria.Hepcidin is an antimicrobial peptide secreted by the liver in response to inflammation. Hepcidin binds to ferroportin mediating its internalization and degradation. Addition of hepcidin to infected macrophages enhanced the intracellular growth of these pathogens. Macrophages from flatiron mice, a strain heterozygous for a loss-of-function ferroportin mutation, showed enhanced intracellular bacterial growth independent of the presence of exogenous hepcidin. Macrophages, from wild-type or flatiron mice, incubated with the oral iron chelator deferriprone or desferasirox showed reduced intracellular bacterial growth suggesting that these chelators might be therapeutic in chronic intracellular bacterial infections. (Blood. 2008;112:866-874) IntroductionHypoferremia is a hallmark of inflammation and results from increased secretion of the liver hormone hepcidin (for review, see Nemeth and Ganz 1 ). Hepcidin is secreted by hepatocytes in response to inflammatory stimuli, notably interleuklin-6 (IL-6). [2][3][4] Hepcidin binds to the iron exporter ferroportin (Fpn), leading to its internalization and degradation. 5 Fpn is the only identified cellular iron exporter and is present on macrophages, absorptive enterocytes, and placenta. Loss of cell surface Fpn results in hypoferremia, which, if persistent, leads to iron-limited erythropoiesis. 6 The hypoferremia of inflammation is thought to represent an antibacterial defense response, as iron acquisition proteins are virulence factors for many species of bacteria. 7 The loss of cell surface Fpn also leads to increased cellular iron, particularly in macrophages that are continuously obtaining iron from senescent red blood cells. The hypoferremia of inflammation may limit the growth of extracellular bacteria but may promote the growth of intracellular bacteria. Support for this hypothesis has been suggested by studies in Salmonellainfected macrophages, where addition of hepcidin promoted the growth of bacteria. 8,9 We show that the growth of 3 other species of intracellular bacteria, Chlamydia psittaci, C trachomatis, and Legionella pneumophila, is promoted by hepcidin-mediated down-regulation of Fpn. Chlamydia spp are obligate intracellular pathogens that have a unique developmental cycle. The infectious forms of Chlamydia spp are termed elementary bodies. After infecting host cells, the elementary bodies differentiate (2-4 hours) within the inclusion membrane to the metabolically active bacteria, termed reticulate bodies, which are noninfectious. The reticulate bodies replicate within the expanding inclusion membrane for approximately 2 to 3 days, differentiate back to element...

show abstract

“…Although in vitro studies suggest bacteriocidal effects of hepcidin, these effects would require concentrations higher than those observed in the circulation. Such concentrations may be achieved locally, for instance in phagosomes of infected macrophages (39 ). Hepcidin might also contribute indirectly to host defense by reducing plasma iron concentrations.…”

Section: Hepcidin Functionmentioning

confidence: 99%

Hepcidin in Human Iron Disorders: Diagnostic Implications

et al. 2011

View full text Add to dashboard Cite

BACKGROUND:The peptide hormone hepcidin plays a central role in regulating dietary iron absorption and body iron distribution. Many human diseases are associated with alterations in hepcidin concentrations. The measurement of hepcidin in biological fluids is therefore a promising tool in the diagnosis and management of medical conditions in which iron metabolism is affected.CONTENT: We describe hepcidin structure, kinetics, function, and regulation. We moreover explore the therapeutic potential for modulating hepcidin expression and the diagnostic potential for hepcidin measurements in clinical practice.

show abstract

Expression and localization of hepcidin in macrophages: a role in host defense against tuberculosis

Cited by 205 publications

References 50 publications

Interferon‐γ limits the availability of iron for intramacrophage Salmonella typhimurium

Interferon‐γ limits the availability of iron for intramacrophage Salmonella typhimurium

Iron depletion limits intracellular bacterial growth in macrophages

Hepcidin in Human Iron Disorders: Diagnostic Implications

Contact Info

Product

Resources

About