The iron export protein ferroportin 1 is differentially expressed in mouse macrophage populations and is present in the mycobacterial-containing phagosome

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

doi:10.1189/jlb.1107781

Cited by 66 publications

(65 citation statements)

References 61 publications

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“…As Fpn is also post-transcriptionally regulated by the IRE/IRP system (see [30] for recent review), our finding of a less marked difference in Fpn protein levels between M1 and M2 macrophages than the difference in the corresponding mRNA at all the time points examined indicates that the Fpn gene is actively transcribed in M2 macrophages and that the impaired translation of Fpn mRNA due to increased IRP2-binding activity is not sufficient to abolish the increase in protein levels. The difference in Fpn regulation between M1 and M2 cells is in line with the recent demonstration that different mouse macrophage subpopulations positively or negatively regulate Fpn expression in response to IFN-g and intracellular pathogens [43]. It is worth noting that the differences in Fpn membrane levels among the various macrophage populations are more marked than those found in total cell extracts (see Fig.…”

Section: Discussionsupporting

confidence: 86%

Differential regulation of iron homeostasis during human macrophage polarized activation

et al. 2010

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Iron metabolism in inflammation has been mostly characterized in macrophages exposed to pathogens or inflammatory conditions, mimicked by the combined action of LPS and IFN-c (M1 polarization). However, macrophages can undergo an alternative type of activation stimulated by Th2 cytokines, and acquire a role in cell growth and tissue repair control (M2 polarization). We characterized the expression of genes related to iron homeostasis in fully differentiated unpolarized (M0), M1 and M2 human macrophages. The molecular signature of the M1 macrophages showed changes in gene expression (ferroportin repression and H ferritin induction) that favour iron sequestration in the reticuloendothelial system, a hallmark of inflammatory disorders, whereas the M2 macrophages had an expression profile (ferroportin upregulation and the downregulation of H ferritin and heme oxygenase) that enhanced iron release. The conditioned media from M2 macrophages promoted cell proliferation more efficiently than those of M1 cells and the effect was blunted by iron chelation. The role of ferroportin-mediated iron release was demonstrated by the absence of differences from the media of macrophages of a patient with loss of function ferroportin mutation. The distinct regulation of iron homeostasis in M2 macrophages provides insights into their role under pathophysiological conditions. Key words: Immune system . Iron . Polarized macrophages IntroductionMacrophages play a critical role in body iron homeostasis by recovering iron from old red blood cells and returning it to the circulation for binding to transferrin, which delivers the metal to the cells that need it for various functions, thus contributing more than 80% to daily iron turnover [1][2][3].Iron retention in the reticuloendothelial system is the main response of body iron homeostasis to inflammation and is regarded as a host's attempt to withhold iron from the invading pathogens [4]. This restricts iron availability for erythroid progenitor cells and may contribute toward causing the common condition of inflammation-related anaemia [1,5,6]. Increased iron retention within inflammatory macrophages is due to increased iron uptake and decreased iron export [7], and is favoured by the induction of the iron storage protein ferritin (Ft) [8,9]. The blockade of macrophage iron release is mainly due to the interaction between the acute phase protein hepcidin and the iron exporter ferroportin (Fpn) [1][2][3], as the increase in circulating hepcidin triggered by inflammatory cytokines causes the internalization and degradation of Fpn [10], the exporter of non-heme iron [11], thus blocking iron release from macrophages.Macrophage Fpn is also negatively regulated at transcriptional and post-transcriptional levels by inflammatory mediators [12][13][14]. It is still unknown whether the inflammatory response affects the feline leukemia virus, subgroup C, receptor that exports heme from macrophages [15] and whether the heme transporter HRG1 proteins play a role in macrophage iron metabolism [16]. O...

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Section: Discussionsupporting

confidence: 86%

Differential regulation of iron homeostasis during human macrophage polarized activation

et al. 2010

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“…Infection with intracellular pathogens results in increased expression of this protein, thus limiting intracellular iron availability. 22,37 This pathway has recently been implicated in the resistance of Hfe Ϫ/Ϫ mice to oral infection with Salmonella in a model of bacterial enterocolitis. 38 In our study, Fpn1 mRNA expression did not differ between Hfe ϩ/ϩ and Hfe Ϫ/Ϫ peritoneal macrophages and was not differentially modulated on infection with Salmonella.…”

Section: Discussionmentioning

confidence: 99%

Absence of functional Hfe protects mice from invasive Salmonella enterica Serovar Typhimurium infection via induction of lipocalin-2

Nairz¹,

Theurl²,

Schroll³

et al. 2009

Blood

133

154

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Mutations of HFE are associated with hereditary hemochromatosis, but their influence on host susceptibility to infection is incompletely understood. We report that mice lacking one or both Hfe alleles are protected from septicemia with Salmonella Typhimurium, displaying prolonged survival and improved control of bacterial replication. This increased resistance is paralleled by an enhanced production of the enterochelin-binding peptide lipocalin-2 (Lcn2), which reduces the availability of iron for Salmonella within Hfe-deficient macrophages. Accordingly, Hfe−/−Lcn2−/− macrophages are unable to efficiently control the infection or to withhold iron from intracellular Salmonella. Correspondingly, the protection conferred by the Hfe defect is abolished in Hfe−/− mice infected with enterochelin-deficient Salmonella as well as in Hfe−/−Lcn2−/− mice infected with wild-type bacteria. Thus, by induction of the iron-capturing peptide Lcn2, absence of functional Hfe confers host resistance to systemic infection with Salmonella, thereby providing an evolutionary advantage which may account for the high prevalence of genetic hemochromatosis.

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“…33 Models exist to explain iron deficiency anemia in mycobacterial diseases such as BU. Notable among them suggests sequestration of Fe 2+ from the body into phagosomes and the lack of NRAMP1 to export the iron back, as the possible cause of the anemia, 34 which could be worsened with an HIV coinfection depending on the clinical stage and state of immunity. 35,36 This study compares the prevalence of HIV infection among confirmed BU patients at a district hospital in Ghana with the general population of patients in that same facility and also describes BU/HIV coinfection cases highlighting the challenges associated with the management of BU/HIV coinfection.…”

Section: Introductionmentioning

confidence: 99%

Challenges Associated with Management of Buruli Ulcer/Human Immunodeficiency Virus Coinfection in a Treatment Center in Ghana: A Case Series Study

Tuffour

Owusu-Mireku

Ruf

et al. 2015

The American Journal of Tropical Medicine and Hygiene

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Abstract. The synergy between Mycobacterium tuberculosis infection and human immunodeficiency virus (HIV)/ acquired immunodeficiency syndrome is well established but not so in Buruli ulcer (BU). We screened confirmed BU cases for HIV infection and followed seven BU/HIV-coinfected patients. Management of BU/HIV was based on the World Health Organization guidelines and patient condition. The HIV positivity among BU patients (8.2%; 11/134) was higher compared with that of general patients attending the facility (4.8%; 718/14,863; P = 0.07) and that of pregnant women alone (2.5%; 279/11,125; P = 0.001). All seven BU/HIV-coinfected cases enrolled in the study presented with very large (category III) lesions with four having multiple lesions compared with 54.5% of category III lesions among HIV-negative BU patients. During the recommended BU treatment with streptomycin and rifampicin (SR) all patients developed immune infiltrates including CD4 T cells in their lesions. However, one patient who received antiretroviral therapy (ART) 1 week after beginning SR treatment developed four additional lesions during antibiotic treatment, while two out of the four who did not receive ART died. Further evidence is required to ascertain the most appropriate time to commence ART in relation to SR treatment to minimize paradoxical reactions.

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The iron export protein ferroportin 1 is differentially expressed in mouse macrophage populations and is present in the mycobacterial-containing phagosome

Cited by 66 publications

References 61 publications

Differential regulation of iron homeostasis during human macrophage polarized activation

Differential regulation of iron homeostasis during human macrophage polarized activation

Absence of functional Hfe protects mice from invasive Salmonella enterica Serovar Typhimurium infection via induction of lipocalin-2

Challenges Associated with Management of Buruli Ulcer/Human Immunodeficiency Virus Coinfection in a Treatment Center in Ghana: A Case Series Study

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