Erythroferrone contributes to hepcidin repression in a mouse model of malarial anemia.
Ontology highlight
ABSTRACT:
SUBMITTER: Latour C
PROVIDER: S-EPMC5210233 | biostudies-other | 2017 Jan
REPOSITORIES: biostudies-other
Publications
Erythroferrone contributes to hepcidin repression in a mouse model of malarial anemia.
Latour Chloé C Wlodarczyk Myriam F MF Jung Grace G Gineste Aurélie A Blanchard Nicolas N Ganz Tomas T Roth Marie-Paule MP Coppin Hélène H Kautz Léon L
Haematologica 20160922 1
Malaria, a major global health challenge worldwide, is accompanied by a severe anemia secondary to hemolysis and increased erythrophagocytosis. Iron is an essential functional component of erythrocyte hemoglobin and its availability is controlled by the liver-derived hormone hepcidin. We examined the regulation of hepcidin during malarial infection in mice using the rodent parasite Plasmodium berghei K173. Mice infected with Plasmodium berghei K173 develop a severe anemia and die after 18 to 22 ...[more]
Similar Datasets
Project description:Intensive care unit (ICU) anemia is an extreme version of anemia of inflammation that occurs commonly in critically ill patients and is associated with increased morbidity and mortality. Currently available therapies for ICU anemia have shown inconsistent efficacies in clinical trials. We conducted a systematic study of the effects of early versus delayed iron (Fe) and/or erythropoietin (EPO) therapy in our previously characterized mouse model of ICU anemia based on an injection of heat-killed Brucella abortus. To study the effects of ongoing inflammation on the response to therapy, inflamed wild-type (WT) and hepcidin knockout (HKO) mice were treated at either early (days 1 and 2) or delayed (days 7 and 8) time points after the inflammatory stimulus. In the early treatment group, Fe and/or EPO therapy did not increase hemoglobin (Hgb) levels or reticulocyte production in either the inflamed WT or HKO groups. In the delayed treatment group, combination Fe?+?EPO therapy did increase Hgb and reticulocyte production in WT mice (mean ?Hgb in WT saline group -9.2?g/dL vs. Fe/EPO -5.5?g/dL; P?<?0.001). The HKO mice in the delayed treatment group did not improve their Hgb, but HKO mice in all treatment groups developed a milder anemia than the WT mice. Our findings indicate that combination Fe?+?EPO therapy is effective in partially reversing ICU anemia when administered after the phase of acute inflammation. Hepcidin ablation alone was more effective in attenuating ICU anemia than Fe?+?EPO therapy, which indicates the potential of antihepcidin therapeutics in treating ICU anemia.
| S-EPMC5603371 | biostudies-literature
Project description:As a pilot study to investigate whether personalized medicine approaches could have value for the reduction of malaria-related mortality in young children, we evaluated questionnaire and biomarker data collected from the Mother Offspring Malaria Study Project birth cohort (Muheza, Tanzania, 2002-2006) at the time of delivery as potential prognostic markers for pediatric severe malarial anemia. Severe malarial anemia, defined here as a Plasmodium falciparum infection accompanied by hemoglobin levels below 50 g/L, is a key manifestation of life-threatening malaria in high transmission regions. For this study sample, a prediction model incorporating cord blood levels of interleukin-1β provided the strongest discrimination of severe malarial anemia risk with a C-index of 0.77 (95% CI 0.70-0.84), whereas a pragmatic model based on sex, gravidity, transmission season at delivery, and bed net possession yielded a more modest C-index of 0.63 (95% CI 0.54-0.71). Although additional studies, ideally incorporating larger sample sizes and higher event per predictor ratios, are needed to externally validate these prediction models, the findings provide proof of concept that risk score-based screening programs could be developed to avert severe malaria cases in early childhood.
| S-EPMC5732579 | biostudies-literature
Project description:Iron is crucial for many biological functions, but quantitatively the most important use of iron is in the production of hemoglobin in red blood cell precursors. The amount of iron in the plasma, and hence its availability for hemoglobin synthesis, is determined by the liver-derived iron regulatory hormone hepcidin. When the iron supply to erythroid precursors is limited, as often occurs during stimulated erythropoiesis, these cells produce signals to inhibit hepatic hepcidin production, thereby increasing the amount of iron that enters the plasma. How stimulated erythropoiesis suppresses hepcidin production is incompletely understood, but erythroferrone, Gdf15 and Twsg1 have emerged as candidate regulatory molecules. To further examine the relationship between erythropoiesis and the candidate erythroid regulators, we have studied five mouse models of anemia, including two models of ?-thalassemia (Hbbth3/+ and RBC14), the hemoglobin deficit mouse (hbd), dietary iron deficient mice and mice treated with phenylhydrazine to induce acute hemolysis. Hematological parameters, iron status and the expression of Erfe (the gene encoding erythroferrone), Gdf15 and Twsg1 in the bone marrow and spleen were examined. Erfe expression was the most consistently upregulated of the candidate erythroid regulators in all of the mouse models examined. Gene expression was particularly high in the bone marrow and spleen of iron deficient animals, making erythroferrone an ideal candidate erythroid regulator, as its influence is strongest when iron supply to developing erythroid cells is limited. Gdf15 expression was also upregulated in most of the anemia models studied although the magnitude of the increase was generally less than that of Erfe. In contrast, very little regulation of Twsg1 was observed. These results support the prevailing hypothesis that erythroferrone is a promising erythroid regulator and demonstrate that Erfe expression is stimulated most strongly when the iron supply to developing erythroid cells is compromised.
| S-EPMC5279787 | biostudies-literature
Project description:BackgroundThe contribution of pro-inflammatory cytokines to the pathogenesis of malarial anemia has been studied extensively but the roles of Th2 cytokines remain unknown. Here, we investigated the role of signal transducer and activator of transcription (STAT)6-mediated responses in erythropoietic suppression during acute malaria infection in mice.Design and methodsNaïve and/or erythropoietin-treated wild-type and STAT6(-/-) mice were infected with Plasmodium chabaudi AS (P. chabaudi), and the effects parasitemia, hematologic parameters, erythropoietin receptor, TER119, and CD71 expression, in vitro erythropoietin-stimulated proliferation of splenic erythroid precursors, and serum cytokine levels were analyzed. To explore the role of interleukin-4 in STAT6-dependent erythropoietic suppression, mice were treated in vivo with a monoclonal antibody to interleukin-4 and the effects on parasitemia, hematologic parameters, and cytokine levels were analyzed.ResultsInfected STAT6(-/-) mice developed enhanced reticulocytosis compared to wild-type mice despite higher parasitemia and a similar course of anemia. Enhanced reticulocytosis in infected STAT6(-/-) mice was associated with an increased frequency of late-stage erythroblasts, fewer leukocytes expressing CD71, and increased erythropoietin-stimulated proliferation of splenocytes compared to infected wild-type mice. Interleukin-4-depleted wild-type mice had increased levels of parasitemia and a course of reticulocytosis similar to responses observed in infected STAT6(-/-) mice. Determination of serum cytokine levels in STAT6(-/-) and wild-type mice depleted of interleukin-4 by treatment with mAb revealed significantly lower levels of interferon-gamma compared to control wild-type mice during infection.ConclusionsTogether, these findings provide evidence for a STAT6-dependent mechanism in mediating erythropoietic suppression during acute blood-stage malaria and indicate a role for interleukin-4 and possibly interferon-gammain STAT6-induced erythropoietic suppression.
| S-EPMC2635397 | biostudies-literature
Project description:Hepcidin, the master regulator of systemic iron homeostasis, tightly influences erythrocyte production. High hepcidin levels block intestinal iron absorption and macrophage iron recycling, causing iron restricted erythropoiesis and anemia. Low hepcidin levels favor bone marrow iron supply for hemoglobin synthesis and red blood cells production. Expanded erythropoiesis, as after hemorrhage or erythropoietin treatment, blocks hepcidin through an acute reduction of transferrin saturation and the release of the erythroblast hormone and hepcidin inhibitor erythroferrone. Quantitatively reduced erythropoiesis, limiting iron consumption, increases transferrin saturation and stimulates hepcidin transcription. Deregulation of hepcidin synthesis is associated with anemia in three conditions: iron refractory iron deficiency anemia (IRIDA), the common anemia of acute and chronic inflammatory disorders, and the extremely rare hepcidin-producing adenomas that may develop in the liver of children with an inborn error of glucose metabolism. Inappropriately high levels of hepcidin cause iron-restricted or even iron-deficient erythropoiesis in all these conditions. Patients with IRIDA or anemia of inflammation do not respond to oral iron supplementation and show a delayed or partial response to intravenous iron. In hepcidin-producing adenomas, anemia is reverted by surgery. Other hepcidin-related anemias are the "iron loading anemias" characterized by ineffective erythropoiesis and hepcidin suppression. This group of anemias includes thalassemia syndromes, congenital dyserythropoietic anemias, congenital sideroblastic anemias, and some forms of hemolytic anemias as pyruvate kinase deficiency. The paradigm is non-transfusion-dependent thalassemia where the release of erythroferrone from the expanded pool of immature erythroid cells results in hepcidin suppression and secondary iron overload that in turn worsens ineffective erythropoiesis and anemia. In thalassemia murine models, approaches that induce iron restriction ameliorate both anemia and the iron phenotype. Manipulations of hepcidin might benefit all the above-described anemias. Compounds that antagonize hepcidin or its effect may be useful in inflammation and IRIDA, while hepcidin agonists may improve ineffective erythropoiesis. Correcting ineffective erythropoiesis in animal models ameliorates not only anemia but also iron homeostasis by reducing hepcidin inhibition. Some targeted approaches are now in clinical trials: hopefully they will result in novel treatments for a variety of anemias.
| S-EPMC6794341 | biostudies-literature
Project description:Greater than 80% of malaria-related mortality occurs in sub-Saharan Africa due to infections with Plasmodium falciparum. The majority of P. falciparum-related mortality occurs in immune-naïve infants and young children, accounting for 18% of all deaths before five years of age. Clinical manifestations of severe falciparum malaria vary according to transmission intensity and typically present as one or more life-threatening complications, including: hyperparasitemia; hypoglycemia; cerebral malaria; severe malarial anemia (SMA); and respiratory distress. In holoendemic transmission areas, SMA is the primary clinical manifestation of severe childhood malaria, with cerebral malaria occurring only in rare cases. Mortality rates from SMA can exceed 30% in pediatric populations residing in holoendemic transmission areas. Since the vast majority of the morbidity and mortality occurs in immune-naïve African children less than five years of age, with SMA as the primary manifestation of severe disease, this review will focus primarily on the innate immune mechanisms that govern malaria pathogenesis in this group of individuals. The pathophysiological processes that contribute to SMA involve direct and indirect destruction of parasitized and non-parasitized red blood cells (RBCs), inefficient and/or suppression of erythropoiesis, and dyserythropoiesis. While all of these causal etiologies may contribute to reduced hemoglobin (Hb) concentrations in malaria-infected individuals, data from our laboratory and others suggest that SMA in immune-naïve children is characterized by a reduced erythropoietic response. One important cause of impaired erythroid responses in children with SMA is dysregulation in the innate immune response. Phagocytosis of malarial pigment hemozoin (Hz) by monocytes, macrophages, and neutrophils is a central factor for promoting dysregulation in innate inflammatory mediators. As such, the role of P. falciparum-derived Hz (PfHz) in mediating suppression of erythropoiesis through its ability to cause dysregulation in pro- and anti-inflammatory cytokines, growth factors, chemokines, and effector molecules is discussed in detail. An improved understanding of the etiological basis of suppression of erythropoietic responses in children with SMA may offer the much needed therapeutic alternatives for control of this global disease burden.
| S-EPMC3221949 | biostudies-literature
Project description:Hemolysis occurring in hematologic diseases is often associated with an iron loading anemia. This iron overload is the result of a massive outflow of hemoglobin into the bloodstream, but the mechanism of hemoglobin handling has not been fully elucidated. Here, in a congenital erythropoietic porphyria mouse model, we evaluate the impact of hemolysis and regenerative anemia on hepcidin synthesis and iron metabolism. Hemolysis was confirmed by a complete drop in haptoglobin, hemopexin and increased plasma lactate dehydrogenase, an increased red blood cell distribution width and osmotic fragility, a reduced half-life of red blood cells, and increased expression of heme oxygenase 1. The erythropoiesis-induced Fam132b was increased, hepcidin mRNA repressed, and transepithelial iron transport in isolated duodenal loops increased. Iron was mostly accumulated in liver and spleen macrophages but transferrin saturation remained within the normal range. The expression levels of hemoglobin-haptoglobin receptor CD163 and hemopexin receptor CD91 were drastically reduced in both liver and spleen, resulting in heme- and hemoglobin-derived iron elimination in urine. In the kidney, the megalin/cubilin endocytic complex, heme oxygenase 1 and the iron exporter ferroportin were induced, which is reminiscent of significant renal handling of hemoglobin-derived iron. Our results highlight ironbound hemoglobin urinary clearance mechanism and strongly suggest that, in addition to the sequestration of iron in macrophages, kidney may play a major role in protecting hepatocytes from iron overload in chronic hemolysis.
| S-EPMC5286934 | biostudies-literature
Project description:Anemia is prevalent in patients with infections and other inflammatory conditions. Induction of the iron regulatory hormone hepcidin has been implicated in the pathogenesis of anemia of inflammation. This review outlines recent discoveries in understanding how hepcidin and its receptor ferroportin are regulated, how they contribute to anemia of inflammation, and how this knowledge may help guide new diagnostic and therapeutic strategies for this disease.IL-6 is a primary driver for hepcidin induction in many models of anemia of inflammation, but the SMAD1/5/8 pathway also contributes, likely via Activin B and SMAD-STAT3 interactions at the hepcidin promoter. Hepcidin has an important functional role in many, but not all forms of anemia of inflammation, although hepcidin-independent mechanisms also contribute. In certain populations, hepcidin assays may help target therapy with iron or erythropoiesis-stimulating agents to patients who may benefit most. New therapies targeting the hepcidin-ferroportin axis have shown efficacy in preclinical and early clinical studies.Recent studies confirm an important role for the hepcidin-ferroportin axis in the development of anemia of inflammation, but also highlight the diverse and complex pathogenesis of this disorder depending on the underlying disease. Hepcidin-based diagnostic and therapeutic strategies offer promise to improve anemia treatment, but more work is needed in this area.
| S-EPMC4993159 | biostudies-literature
Project description:A novel humanized mouse model of Cooley's Anemia (CA) was generated by targeted gene replacement in embryonic stem (ES) cells. Because the mouse does not have a true fetal hemoglobin, a delayed switching human gamma to beta(0) globin gene cassette (gammabeta(0)) was inserted directly into the murine beta globin locus replacing both adult mouse beta globin genes. The inserted human beta(0) globin allele has a mutation in the splice donor site that produces the same aberrant transcripts in mice as described in human cells. No functional human beta globin polypeptide chains are produced. Heterozygous gammabeta(0) mice suffer from microcytic anemia. Unlike previously described animal models of beta thalassemia major, homozygous gammabeta(0) mice switch from mouse embryonic globin chains to human fetal gamma globin during fetal life. When bred with human alpha globin knockin mice, homozygous CA mice survive solely upon human fetal hemoglobin at birth. This preclinical animal model of CA can be utilized to study the regulation of globin gene expression, synthesis, and switching; the reactivation of human fetal globin gene expression; and the testing of genetic and cell-based therapies for the correction of thalassemia.
| S-EPMC2643510 | biostudies-literature
Project description:We examined changes in hepcidin (closely associated with anemia of chronic inflammation (ACI)) and upstream regulatory pathways after intravenous (IV) iron supplementation in an ACI animal model. ACI was induced in male Sprague-Dawley rats by intraperitoneally administering complete Freund's adjuvant (CFA). Two weeks after starting CFA treatment, ACI rats received IV iron (CFA-iron) or vehicle (CFA-saline). Three days after IV iron treatment, iron profiles, hepcidin levels, and expression of proteins involved in the signaling pathways upstream of hepcidin transcription in the liver were measured. In CFA-treated rats, anemia with a concomitant increase in the levels of serum inflammatory cytokines and reactive oxygen species occurred. In CFA-iron rats, hemoglobin (Hb) concentration was still lower than that in control rats. In CFA-saline rats, hepatic hepcidin and ferritin levels increased compared with those in control rats and were further increased in CFA-iron rats. In CFA-saline rats, NADPH oxidase- (NOX-) 2, NOX-4, and superoxide dismutase levels in the liver were upregulated compared with those in control rats and their levels were further increased in CFA-iron rats. In CFA-saline rats, activities of the IL-6/STAT and BMP/SMAD pathways were enhanced in the liver compared with those in control rats and their levels were further increased in CFA-iron rats, whereas IL-6 expression remained unaffected after IV iron administration. In HepG2 cells, iron caused phosphorylation of STAT-3 and SMAD1/5 and knockdown of STAT-3 and SMAD1/5 using siRNAs reduced iron-induced hepcidin upregulation to levels similar to those in corresponding control cells. Renal erythropoietin expression and serum erythroferrone concentration were lower in CFA-iron rats than those in control rats. In ACI rats, IV iron supplementation did not recover Hb within three days despite an increase in hepatic ferritin levels, which might be attributable to an additional increase in hepcidin levels that was already upregulated under ACI conditions. Both STAT-3 phosphorylation and SMAD1/5 phosphorylation were associated with hepcidin upregulation after IV iron treatment, and this seems to be linked to iron-induced oxidative stress.
| S-EPMC8643261 | biostudies-literature