The iron-regulatory hormone hepcidin is induced early in infection, causing iron sequestration in macrophages and decreased plasma iron; this is proposed to limit the replication of extracellular ...microbes, but could also promote infection with macrophage-tropic pathogens. The mechanisms by which hepcidin and hypoferremia modulate host defense, and the spectrum of microbes affected, are poorly understood. Using mouse models, we show that hepcidin was selectively protective against siderophilic extracellular pathogens (Yersinia enterocolitica O9) by controlling non–transferrin-bound iron (NTBI) rather than iron-transferrin concentration. NTBI promoted the rapid growth of siderophilic but not nonsiderophilic bacteria in mice with either genetic or iatrogenic iron overload and in human plasma. Hepcidin or iron loading did not affect other key components of innate immunity, did not indiscriminately promote intracellular infections (Mycobacterium tuberculosis), and had no effect on extracellular nonsiderophilic Y enterocolitica O8 or Staphylococcus aureus. Hepcidin analogs may be useful for treatment of siderophilic infections.
•In mouse models, hepcidin participates in innate immunity by controlling NTBI.•NTBI-dependent infections can be treated with hepcidin agonists in mouse models of hereditary hemochromatosis or parenteral iron overload.
Highlights • The hormone hepcidin regulates systemic iron homeostasis. • Hepcidin deficiency or excess contributes to the pathogenesis of iron disorders. • Hepcidin agonists and antagonists are being ...developed as novel therapeutics.
Erythropoiesis is the predominant consumer of iron in humans and other vertebrates. By decreasing the transcription of the gene encoding the iron-regulatory hormone hepcidin, erythropoietic activity ...stimulates iron absorption, as well as the release of iron from recycling macrophages and from stores in hepatocytes. The main erythroid regulator of hepcidin is erythroferrone (ERFE), synthesized and secreted by erythroblasts in the marrow and extramedullary sites. The production of ERFE is induced by erythropoietin (EPO) and is also proportional to the total number of responsive erythroblasts. ERFE acts on hepatocytes to suppress the production of hepcidin, through an as yet unknown mechanism that involves the bone morphogenetic protein pathway. By suppressing hepcidin, ERFE facilitates iron delivery during stress erythropoiesis but also contributes to iron overload in anemias with ineffective erythropoiesis. Although most of these mechanisms have been defined in mouse models, studies to date indicate that the pathophysiology of ERFE is similar in humans. ERFE antagonists and mimics may prove useful for the prevention and treatment of iron disorders.
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•Systemic iron homeostasis is controlled by the peptide hormone hepcidin.•Hepcidin binds to iron exporter ferroportin to control iron efflux into plasma.•Systemic iron homeostasis is closely coupled to erythropoiesis.•Erythroferrone is a glycoprotein secreted by erythropoietin-primed erythroblasts.•Erythroferrone signals erythroid demand for iron by suppressing hepcidin production.
Iron deficiency is common worldwide and is associated with adverse pregnancy outcomes. The increasing prevalence of indiscriminate iron supplementation during pregnancy also raises concerns about the ...potential adverse effects of iron excess. We examined how maternal iron status affects the delivery of iron to the placenta and fetus. Using mouse models, we documented maternal homeostatic mechanisms that protect the placenta and fetus from maternal iron excess. We determined that under physiological conditions or in iron deficiency, fetal and placental hepcidin did not regulate fetal iron endowment. With maternal iron deficiency, critical transporters mediating placental iron uptake (transferrin receptor 1 TFR1) and export (ferroportin FPN) were strongly regulated. In mice, not only was TFR1 increased, but FPN was surprisingly decreased to preserve placental iron in the face of fetal iron deficiency. In human placentas from pregnancies with mild iron deficiency, TFR1 was increased, but there was no change in FPN. However, induction of more severe iron deficiency in human trophoblast in vitro resulted in the regulation of both TFR1 and FPN, similar to what was observed in the mouse model. This placental adaptation that prioritizes placental iron is mediated by iron regulatory protein 1 (IRP1) and is important for the maintenance of mitochondrial respiration, thus ultimately protecting the fetus from the potentially dire consequences of generalized placental dysfunction.
Hydrogen sulfide (H2S) has a significant effect on the regulation of interleukin‐6 (IL‐6) and signal transducer and activator of transcription 3 (STAT3) activities, while IL‐6 directly regulates ...hepcidin expression via STAT3. We therefore hypothesized that H
2S has a role in body iron homeostasis by regulating the expression of iron transport proteins via the IL‐6/STAT3/Hepcidin pathway. Here, we investigated the effects of two H
2S donors sodium hydrosulfide and GYY4137 on the expression of ferroportin‐1 (Fpn1), transferrin receptor‐1 (TfR1), hepcidin, IL‐6 and pSTAT3 in the spleen of mice in vivo and peritoneal macrophage in vitro. We also examined the effects of H
2S on serum iron, transferrin saturation, and ferritin light chain contents in the spleen, and on nitrite content, nuclear factor erythroid 2‐related factor‐2 (Nrf2) and iron regulatory protein 1 (IRP1) in the macrophages. We demonstrated that H
2S regulates the expression of TfR1 and Fpn1 in the spleen in vivo and in peritoneal macrophages in vitro predominantly via the IL‐6/pSTAT3/hepcidin pathway, under the conditions of inflammation induced by lipopolysaccharides. We also provide evidence that under uninflamed conditions, the regulation of Fpn1 and TfR1 expression by H
2S, both in vivo and in vitro, are mediated by the nitric oxide (NO)/Nrf2 and iron regulatory protein/iron responsive element pathways, respectively, which are independent of IL‐6/pSTAT3/hepcidin signals. These findings show that H
2S is a key player in iron homeostasis under not only the inflamed conditions but also uninflamed conditions.
H2S regulates the expression of TfR1 and Fpn1 in the spleen in vivo and in peritoneal macrophages in vitro predominantly via the IL‐6/pSTAT3/hepcidin pathway, under the conditions of inflammation. Under uninflamed conditions, the regulation of Fpn1 and TfR1 expression by H
2S, both in vivo and in vitro, are mediated by the NO/Nrf2 and iron regulatory protein/iron responsive element pathways, respectively, which are independent of IL‐6/pSTAT3/hepcidin signals. These findings show that H
2S is a key player in iron homeostasis under not only the inflamed conditions but also uninflamed conditions.
Nanoparticles (NPs) have been utilized to deliver drugs to the intestinal epithelium in vivo. Moreover, NPs derived from edible plants are less toxic than synthetic NPs. Here, we utilized ginger ...NP-derived lipid vectors (GDLVs) in a proof-of-concept investigation to test the hypothesis that inhibiting expression of divalent metal-ion transporter 1 (Dmt1) would attenuate iron loading in a mouse model of hereditary hemochromatosis (HH). Initial experiments using duodenal epithelial organ cultures from intestine-specific Dmt1 knockout (KO) (Dmt1int/int) mice in the Ussing chamber established that Dmt1 is the only active iron importer during iron-deficiency anemia. Further, when Dmt1int/int mice were crossed with mice lacking the iron-regulatory hormone, hepcidin (Hepc−/−), iron loading was abolished. Hence, intestinal Dmt1 is required for the excessive iron absorption that typifies HH. Additional experiments established a protocol to produce GDLVs carrying functional Dmt1 small interfering RNAs (siRNAs) and to target these gene delivery vehicles to the duodenal epithelium in vivo (by incorporating folic acid FA). When FA-GDLVs carrying Dmt1 siRNA were administered to weanling Hepc−/− mice for 16 days, intestinal Dmt1 mRNA expression was attenuated and tissue iron accumulation was blunted. Oral delivery of functional siRNAs by FA-GDLVs is a suitable therapeutic approach to mitigate iron loading in murine HH.
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Collins and colleagues developed a novel experimental technique to mitigate excess iron accumulation in hepcidin knockout (KO) mice, which model human hereditary hemochromatosis. The approach involved oral intragastric gavage of lipid nanoparticles derived from edible ginger to deliver small interfering RNAs (siRNAs) targeting the main intestinal iron transporter Dmt1.
Background.
The mechanisms by which testosterone increases hemoglobin and hematocrit remain unclear.
Methods.
We assessed the hormonal and hematologic responses to testosterone administration in a ...clinical trial in which older men with mobility limitation were randomized to either placebo or testosterone gel daily for 6 months.
Results.
The 7%–10% increase in hemoglobin and hematocrit, respectively, with testosterone administration was associated with significantly increased erythropoietin (EPO) levels and decreased ferritin and hepcidin levels at 1 and 3 months. At 6 months, EPO and hepcidin levels returned toward baseline in spite of continued testosterone administration, but EPO levels remained nonsuppressed even though elevated hemoglobin and hematocrit higher than at baseline, suggesting a new set point. Consistent with increased iron utilization, soluble transferrin receptor (sTR) levels and ratio of sTR/log ferritin increased significantly in testosterone-treated men. Hormonal and hematologic responses were similar in anemic participants. The majority of testosterone-treated anemic participants increased their hemoglobin into normal range.
Conclusions.
Testosterone-induced increase in hemoglobin and hematocrit is associated with stimulation of EPO and reduced ferritin and hepcidin concentrations. We propose that testosterone stimulates erythropoiesis by stimulating EPO and recalibrating the set point of EPO in relation to hemoglobin and by increasing iron utilization for erythropoiesis.
In β-thalassemia and polycythemia vera (PV), disordered erythropoiesis triggers severe pathophysiological manifestations. β-Thalassemia is characterized by ineffective erythropoiesis, reduced ...production of erythrocytes, anemia, and iron overload and PV by erythrocytosis and thrombosis. Minihepcidins are hepcidin agonists that have been previously shown to prevent iron overload in murine models of hemochromatosis and induce iron-restricted erythropoiesis at higher doses. Here, we show that in young Hbbth3/+ mice, which serve as a model of untransfused β-thalassemia, minihepcidin ameliorates ineffective erythropoiesis, anemia, and iron overload. In older mice with untransfused β-thalassemia, minihepcidin improves erythropoiesis and does not alter the beneficial effect of the iron chelator deferiprone on iron overload. In PV mice that express the orthologous JAK2 mutation causing human PV, administration of minihepcidin significantly reduces splenomegaly and normalizes hematocrit levels. These studies indicate that drug-like minihepcidins have a potential as future therapeutics for untransfused β-thalassemia and PV.
•Investigation of the iron-restrictive effect of minihepcidin peptides in the treatment of β-thalassemia and polycythemia vera.
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Atherosclerotic cardiovascular disease is a major burden on global health and a leading cause of death worldwide. The pathophysiology of this chronic disease is complex, involving ...inflammation, lipoprotein oxidation and accumulation, plaque formation, and calcification. In 1981, Dr. Jerome Sullivan formulated the ‘Iron Hypothesis’, suggesting that higher levels of stored iron promote cardiovascular diseases, whereas iron deficiency may have an atheroprotective effect. This hypothesis has stimulated research focused on clarifying the role of iron in the development of atherosclerosis. However, preclinical and clinical studies have produced contradictory results and the observation that patients with hemochromatosis do not appear to have an increased risk of atherosclerosis seemed incongruous with Sullivan’s initial hypothesis. The ‘paradox’ of systemic iron overload not being accompanied by an increased risk for atherosclerosis led to a refinement of the iron hypothesis focusing on intracellular macrophage iron. More recent in vitro and animal studies have elucidated the complex signaling pathways regulating iron, with a particular focus on hepcidin, the master regulator of body iron homeostasis. Bone morphogenetic protein (BMP) signaling is the major pathway that is required for induction of hepcidin expression in response to increasing levels of iron. Strong links between iron homeostasis, BMP signaling, inflammation and atherosclerosis have been established in both mechanistic and human studies. This review summarizes the current understanding of the role of iron homeostasis and hepcidin in the development of atherosclerosis and discusses the BMP-hepcidin-ferroportin axis as a novel therapeutic target for the treatment of cardiovascular disease.
Iron deficiency Pasricha, Sant-Rayn; Tye-Din, Jason; Muckenthaler, Martina U ...
The Lancet (British edition),
01/2021, Letnik:
397, Številka:
10270
Journal Article
Recenzirano
Iron deficiency is one of the leading contributors to the global burden of disease, and particularly affects children, premenopausal women, and people in low-income and middle-income countries. ...Anaemia is one of many consequences of iron deficiency, and clinical and functional impairments can occur in the absence of anaemia. Iron deprivation from erythroblasts and other tissues occurs when total body stores of iron are low or when inflammation causes withholding of iron from the plasma, particularly through the action of hepcidin, the main regulator of systemic iron homoeostasis. Oral iron therapy is the first line of treatment in most cases. Hepcidin upregulation by oral iron supplementation limits the absorption efficiency of high-dose oral iron supplementation, and of oral iron during inflammation. Modern parenteral iron formulations have substantially altered iron treatment and enable rapid, safe total-dose iron replacement. An underlying cause should be sought in all patients presenting with iron deficiency: screening for coeliac disease should be considered routinely, and endoscopic investigation to exclude bleeding gastrointestinal lesions is warranted in men and postmenopausal women presenting with iron deficiency anaemia. Iron supplementation programmes in low-income countries comprise part of the solution to meeting WHO Global Nutrition Targets.
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