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In vivo bioluminescence imaging of labile iron accumulation in a murine model of infection.
Aron AT, Heffern MC, Lonergan ZR, Vander Wal MN, Blank BR, Spangler B, Zhang Y, Park HM, Stahl A, Renslo AR, Skaar EP, Chang CJ
(2017) Proc Natl Acad Sci U S A 114: 12669-12674
MeSH Terms: 2,2'-Dipyridyl, Acinetobacter Infections, Acinetobacter baumannii, Anemia, Iron-Deficiency, Animals, Cation Transport Proteins, Cations, Divalent, Disease Models, Animal, Ferric Compounds, Firefly Luciferin, Fluorescent Dyes, Gene Expression Regulation, Hepcidins, Homeostasis, Iron, Iron Overload, Iron Regulatory Protein 1, Iron Regulatory Protein 2, Luminescent Measurements, Mice, Mice, Transgenic, Quaternary Ammonium Compounds, Receptors, Transferrin, Signal Transduction, Transferrin
Show Abstract · Added March 15, 2018
Iron is an essential metal for all organisms, yet disruption of its homeostasis, particularly in labile forms that can contribute to oxidative stress, is connected to diseases ranging from infection to cancer to neurodegeneration. Iron deficiency is also among the most common nutritional deficiencies worldwide. To advance studies of iron in healthy and disease states, we now report the synthesis and characterization of iron-caged luciferin-1 (ICL-1), a bioluminescent probe that enables longitudinal monitoring of labile iron pools (LIPs) in living animals. ICL-1 utilizes a bioinspired endoperoxide trigger to release d-aminoluciferin for selective reactivity-based detection of Fe with metal and oxidation state specificity. The probe can detect physiological changes in labile Fe levels in live cells and mice experiencing iron deficiency or overload. Application of ICL-1 in a model of systemic bacterial infection reveals increased iron accumulation in infected tissues that accompany transcriptional changes consistent with elevations in both iron acquisition and retention. The ability to assess iron status in living animals provides a powerful technology for studying the contributions of iron metabolism to physiology and pathology.
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25 MeSH Terms
Hepcidin-ferroportin axis controls toll-like receptor 4 dependent macrophage inflammatory responses in human atherosclerotic plaques.
Habib A, Polavarapu R, Karmali V, Guo L, Van Dam R, Cheng Q, Akahori H, Saeed O, Nakano M, Pachura K, Hong CC, Shin E, Kolodgie F, Virmani R, Finn AV
(2015) Atherosclerosis 241: 692-700
MeSH Terms: Animals, Antigens, CD, Antigens, Differentiation, Myelomonocytic, Cation Transport Proteins, Foam Cells, Haptoglobins, Hemoglobins, Hepcidins, Humans, Inflammation, Iron, Lipopolysaccharides, Lipoproteins, LDL, Macrophages, Macrophages, Peritoneal, Male, Membrane Microdomains, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Differentiation Factor 88, Plaque, Atherosclerotic, Receptors, Cell Surface, Signal Transduction, Toll-Like Receptor 4, Tumor Necrosis Factor-alpha
Show Abstract · Added July 7, 2015
OBJECTIVES - Toll-like Receptor 4 (TLR4) is implicated in modulating inflammatory cytokines though its role in atherosclerosis remains uncertain. We have recently described a non-foam cell macrophage phenotype driven by ingestion of hemoglobin:haptoglobin complexes (HH), via the scavenger receptor CD163, characterized by reduced inflammatory cytokine production. In this study, we examined the role of iron metabolism in modulating TLR4 signaling in these cells.
METHODS AND RESULTS - Areas in human atherosclerotic plaque with non-foam cell, CD163 positive macrophages demonstrated reduced expression of tumor necrosis factor alpha (TNF-α) and interferon-beta (INF-β) compared to foam cells. Human macrophages differentiated in hemoglobin:haptoglobin (HH) complexes expressed the CD163 positive non-foam cell phenotype and demonstrated significantly less TNF-α and INF-β compared to control macrophages when exposed to oxidized LDL (oxLDL) or lipopolysaccharide (LPS). LPS stimulated expression of TNF-α and INF-β could be restored in HH macrophages by pretreatment with hepcidin, an endogenous suppressor of ferroportin1 (FPN), or by genetic suppression of FPN in macrophages derived from myeloid specific FPN knockout mice. LPS stimulated control macrophages demonstrated increase in TLR4 trafficking to lipid rafts; this response was suppressed in HH macrophages but was restored upon pretreatment with hepcidin. Using a pharmacologic hepcidin suppressor, we observed a decrease in cytokine expression and TLR4-lipid raft trafficking in LPS-stimulated in a murine macrophage model.
CONCLUSION - TLR4 dependent macrophage signaling is controlled via hepcidin-ferroportin1 axis by influencing TLR4-lipid raft interactions. Pharmacologic manipulation of iron metabolism may represent a promising approach to limiting TLR4-mediated inflammatory responses.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
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26 MeSH Terms
A hepcidin lowering agent mobilizes iron for incorporation into red blood cells in an adenine-induced kidney disease model of anemia in rats.
Sun CC, Vaja V, Chen S, Theurl I, Stepanek A, Brown DE, Cappellini MD, Weiss G, Hong CC, Lin HY, Babitt JL
(2013) Nephrol Dial Transplant 28: 1733-43
MeSH Terms: Adenine, Anemia, Iron-Deficiency, Animals, Anti-Infective Agents, Blotting, Western, Bone Morphogenetic Proteins, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Erythrocytes, Erythropoiesis, Hepcidins, Humans, Iron, Kidney Diseases, Male, Pyrazoles, Pyrimidines, RNA, Messenger, Rats, Rats, Wistar, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction
Show Abstract · Added September 20, 2013
BACKGROUND - Anemia is a common complication of chronic kidney disease (CKD) that negatively impacts the quality of life and is associated with numerous adverse outcomes. Excess levels of the iron regulatory hormone hepcidin are thought to contribute to anemia in CKD patients by decreasing iron availability from the diet and from body stores. Adenine treatment in rats has been proposed as an animal model of anemia of CKD with high hepcidin levels that mirrors the condition in human patients.
METHODS - We developed a modified adenine-induced kidney disease model with a higher survival rate than previously reported models, while maintaining persistent kidney disease and anemia. We then tested whether the small molecule bone morphogenetic protein (BMP) inhibitor LDN-193189, which was previously shown to lower hepcidin levels in rodents, mobilized iron into the plasma and improved iron-restricted erythropoiesis in this model.
RESULTS - Adenine-treated rats exhibited increased hepatic hepcidin mRNA, decreased serum iron, increased spleen iron content, low hemoglobin (Hb) and inappropriately low erythropoietin (EPO) levels relative to the degree of anemia. LDN-193189 administration to adenine-treated rats lowered hepatic hepcidin mRNA, mobilized stored iron into plasma and increased Hb content of reticulocytes.
CONCLUSIONS - Our data suggest that hepcidin lowering agents may provide a new therapeutic strategy to improve iron availability for erythropoiesis in CKD.
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22 MeSH Terms
Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis.
Liu Q, Davidoff O, Niss K, Haase VH
(2012) J Clin Invest 122: 4635-44
MeSH Terms: Animals, Antimicrobial Cationic Peptides, Basic Helix-Loop-Helix Transcription Factors, Cell Line, Tumor, Erythropoiesis, Erythropoietin, Gene Expression, Gene Expression Regulation, Growth Differentiation Factor 15, Hepatocytes, Hepcidins, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Hypoxia-Inducible Factor-Proline Dioxygenases, Liver, Mice, Mice, Knockout, Procollagen-Proline Dioxygenase, Von Hippel-Lindau Tumor Suppressor Protein
Show Abstract · Added August 19, 2013
Iron demand in bone marrow increases when erythropoiesis is stimulated by hypoxia via increased erythropoietin (EPO) synthesis in kidney and liver. Hepcidin, a small polypeptide produced by hepatocytes, plays a central role in regulating iron uptake by promoting internalization and degradation of ferroportin, the only known cellular iron exporter. Hypoxia suppresses hepcidin, thereby enhancing intestinal iron uptake and release from internal stores. While HIF, a central mediator of cellular adaptation to hypoxia, directly regulates renal and hepatic EPO synthesis under hypoxia, the molecular basis of hypoxia/HIF-mediated hepcidin suppression in the liver remains unclear. Here, we used a genetic approach to disengage HIF activation from EPO synthesis and found that HIF-mediated suppression of the hepcidin gene (Hamp1) required EPO induction. EPO induction was associated with increased erythropoietic activity and elevated serum levels of growth differentiation factor 15. When erythropoiesis was inhibited pharmacologically, Hamp1 was no longer suppressed despite profound elevations in serum EPO, indicating that EPO by itself is not directly involved in Hamp1 regulation. Taken together, we provide in vivo evidence that Hamp1 suppression by the HIF pathway occurs indirectly through stimulation of EPO-induced erythropoiesis.
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19 MeSH Terms
Treatment of erythropoietin deficiency in mice with systemically administered siRNA.
Querbes W, Bogorad RL, Moslehi J, Wong J, Chan AY, Bulgakova E, Kuchimanchi S, Akinc A, Fitzgerald K, Koteliansky V, Kaelin WG
(2012) Blood 120: 1916-22
MeSH Terms: Anemia, Animals, Antimicrobial Cationic Peptides, Base Sequence, Cells, Cultured, Erythropoiesis, Erythropoietin, Feasibility Studies, Female, Hepcidins, Humans, Hypoxia-Inducible Factor-Proline Dioxygenases, Inflammation, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Procollagen-Proline Dioxygenase, RNA Interference, RNA, Small Interfering, Renal Insufficiency
Show Abstract · Added March 4, 2015
Anemia linked to a relative deficiency of renal erythropoietin production is a significant cause of morbidity and medical expenditures in the developed world. Recombinant erythropoietin is expensive and has been linked to excess cardiovascular events. Moreover, some patients become refractory to erythropoietin because of increased production of factors such as hepcidin. During fetal life, the liver, rather than the kidney, is the major source of erythropoietin. In the present study, we show that it is feasible to reactivate hepatic erythropoietin production and suppress hepcidin levels using systemically delivered siRNAs targeting the EglN prolyl hydroxylases specifically in the liver, leading to improved RBC production in models of anemia caused by either renal insufficiency or chronic inflammation with enhanced hepcidin production.
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23 MeSH Terms
Pharmacological suppression of hepcidin increases macrophage cholesterol efflux and reduces foam cell formation and atherosclerosis.
Saeed O, Otsuka F, Polavarapu R, Karmali V, Weiss D, Davis T, Rostad B, Pachura K, Adams L, Elliott J, Taylor WR, Narula J, Kolodgie F, Virmani R, Hong CC, Finn AV
(2012) Arterioscler Thromb Vasc Biol 32: 299-307
MeSH Terms: ATP Binding Cassette Transporter 1, ATP Binding Cassette Transporter, Subfamily G, Member 1, ATP-Binding Cassette Transporters, Animals, Antimicrobial Cationic Peptides, Apolipoproteins E, Atherosclerosis, Bone Morphogenetic Proteins, Cell Differentiation, Cholesterol, Disease Models, Animal, Foam Cells, Hepcidins, Iron, Lipoproteins, Macrophages, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Pyrazoles, Pyrimidines, Signal Transduction
Show Abstract · Added August 19, 2012
OBJECTIVE - We recently reported that lowering of macrophage free intracellular iron increases expression of cholesterol efflux transporters ABCA1 and ABCG1 by reducing generation of reactive oxygen species. In this study, we explored whether reducing macrophage intracellular iron levels via pharmacological suppression of hepcidin can increase macrophage-specific expression of cholesterol efflux transporters and reduce atherosclerosis.
METHODS AND RESULTS - To suppress hepcidin, increase expression of the iron exporter ferroportin, and reduce macrophage intracellular iron, we used a small molecule inhibitor of bone morphogenetic protein (BMP) signaling, LDN 193189 (LDN). LDN (10 mg/kg IP b.i.d.) was administered to mice, and its effects on atherosclerosis, intracellular iron, oxidative stress, lipid efflux, and foam cell formation were measured in plaques and peritoneal macrophages. Long-term LDN administration to apolipoprotein E-/- mice increased ABCA1 immunoreactivity within intraplaque macrophages by 3.7-fold (n=8; P=0.03), reduced Oil Red O-positive lipid area by 50% (n=8; P=0.02), and decreased total plaque area by 43% (n=8; P=0.001). LDN suppressed liver hepcidin transcription and increased macrophage ferroportin, lowering intracellular iron and hydrogen peroxide production. LDN treatment increased macrophage ABCA1 and ABCG1 expression, significantly raised cholesterol efflux to ApoA-1, and decreased foam cell formation. All preceding LDN-induced effects on cholesterol efflux were reversed by exogenous hepcidin administration, suggesting modulation of intracellular iron levels within macrophages as the mechanism by which LDN triggers these effects.
CONCLUSIONS - These data suggest that pharmacological manipulation of iron homeostasis may be a promising target to increase macrophage reverse cholesterol transport and limit atherosclerosis.
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23 MeSH Terms
Pharmacologic inhibition of hepcidin expression reverses anemia of chronic inflammation in rats.
Theurl I, Schroll A, Sonnweber T, Nairz M, Theurl M, Willenbacher W, Eller K, Wolf D, Seifert M, Sun CC, Babitt JL, Hong CC, Menhall T, Gearing P, Lin HY, Weiss G
(2011) Blood 118: 4977-84
MeSH Terms: Anemia, Animals, Antimicrobial Cationic Peptides, Cells, Cultured, Chronic Disease, Disease Models, Animal, Drug Evaluation, Preclinical, Female, GPI-Linked Proteins, Gene Expression, Hemochromatosis Protein, Hepcidins, Immunoglobulin Fc Fragments, Inflammation, Membrane Proteins, Pyrazoles, Pyrimidines, Rats, Rats, Inbred Lew, Remission Induction
Show Abstract · Added August 19, 2012
Anemia of chronic inflammation (ACI) is the most frequent anemia in hospitalized patients and is associated with significant morbidity. A major underlying mechanism of ACI is the retention of iron within cells of the reticuloendothelial system (RES), thus making the metal unavailable for efficient erythropoiesis. This reticuloendothelial iron sequestration is primarily mediated by excess levels of the iron regulatory peptide hepcidin down-regulating the functional expression of the only known cellular iron export protein ferroportin resulting in blockade of iron egress from these cells. Using a well-established rat model of ACI, we herein provide novel evidence for effective treatment of ACI by blocking endogenous hepcidin production using the small molecule dorsomorphin derivative LDN-193189 or the protein soluble hemojuvelin-Fc (HJV.Fc) to inhibit bone morphogenetic protein-Smad mediated signaling required for effective hepcidin transcription. Pharmacologic inhibition of hepcidin expression results in mobilization of iron from the RES, stimulation of erythropoiesis and correction of anemia. Thus, hepcidin lowering agents are a promising new class of pharmacologic drugs to effectively combat ACI.
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20 MeSH Terms
Regulation of TMPRSS6 by BMP6 and iron in human cells and mice.
Meynard D, Vaja V, Sun CC, Corradini E, Chen S, López-Otín C, Grgurevic L, Hong CC, Stirnberg M, Gütschow M, Vukicevic S, Babitt JL, Lin HY
(2011) Blood 118: 747-56
MeSH Terms: Anemia, Iron-Deficiency, Animals, Antimicrobial Cationic Peptides, Bone Morphogenetic Protein 6, Bone Morphogenetic Protein Receptors, Carcinoma, Hepatocellular, Cell Line, Tumor, Hepcidins, Humans, Iron, Liver Neoplasms, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, RNA, Messenger, Serine Endopeptidases, Signal Transduction
Show Abstract · Added August 19, 2012
Mutations in transmembrane protease, serine 6 (TMPRSS6), encoding matriptase-2, are responsible for the familial anemia disorder iron-refractory iron deficiency anemia (IRIDA). Patients with IRIDA have inappropriately elevated levels of the iron regulatory hormone hepcidin, suggesting that TMPRSS6 is involved in negatively regulating hepcidin expression. Hepcidin is positively regulated by iron via the bone morphogenetic protein (BMP)-SMAD signaling pathway. In this study, we investigated whether BMP6 and iron also regulate TMPRSS6 expression. Here we demonstrate that, in vitro, treatment with BMP6 stimulates TMPRSS6 expression at the mRNA and protein levels and leads to an increase in matriptase-2 activity. Moreover, we identify that inhibitor of DNA binding 1 is the key element of the BMP-SMAD pathway to regulate TMPRSS6 expression in response to BMP6 treatment. Finally, we show that, in mice, Tmprss6 mRNA expression is stimulated by chronic iron treatment or BMP6 injection and is blocked by injection of neutralizing antibody against BMP6. Our results indicate that BMP6 and iron not only induce hepcidin expression but also induce TMPRSS6, a negative regulator of hepcidin expression. Modulation of TMPRSS6 expression could serve as a negative feedback inhibitor to avoid excessive hepcidin increases by iron to help maintain tight homeostatic balance of systemic iron levels.
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18 MeSH Terms
The bone morphogenetic protein-hepcidin axis as a therapeutic target in inflammatory bowel disease.
Wang L, Trebicka E, Fu Y, Ellenbogen S, Hong CC, Babitt JL, Lin HY, Cherayil BJ
(2012) Inflamm Bowel Dis 18: 112-9
MeSH Terms: Animals, Anti-Bacterial Agents, Antimicrobial Cationic Peptides, Blotting, Western, Bone Morphogenetic Protein 6, Colitis, Hepcidins, Inflammatory Bowel Diseases, Interleukin-6, Iron, Male, Mice, Mice, Inbred C57BL, Pyrazoles, Pyrimidines, RNA, Messenger, Real-Time Polymerase Chain Reaction, Signal Transduction, T-Lymphocytes
Show Abstract · Added August 19, 2012
BACKGROUND - A debilitating anemia associated with low serum iron often accompanies inflammatory bowel disease (IBD). Increased production of the iron regulatory hormone hepcidin is implicated in its pathogenesis and may also contribute to the inflammatory process itself. Hepcidin expression is dependent on bone morphogenetic proteins (BMPs) like BMP6, but the mechanisms that increase hepcidin levels during intestinal inflammation are not clear. Here we test the hypothesis that inhibiting hepcidin expression may have beneficial effects in IBD, and also shed light on the mechanism of colitis-induced hepcidin upregulation.
METHODS - Mice with T cell transfer colitis were treated with vehicle or one of three anti-BMP reagents: HJV.Fc, a recombinant protein that prevents binding of BMPs to their receptor, LDN-193189, a small molecule inhibitor of BMP signal transduction, and an anti-BMP6 antibody. The effects of these reagents on colitis severity, liver hepcidin mRNA, and serum iron were determined. The mechanism of hepcidin upregulation was investigated by examining BMP6 expression and activity and the effects of IL-6 deficiency.
RESULTS - All the anti-BMP reagents inhibited hepcidin expression and increased serum iron levels in the colitic mice. They also produced modest reductions in colon inflammatory cytokine expression. Although hepcidin upregulation during colitis was dependent on BMP6, it was not associated with increased BMP6 expression or activity. IL-6 was required for increased hepcidin expression during colitis.
CONCLUSIONS - Inhibiting hepcidin expression may help to correct the anemia of IBD and may also attenuate intestinal inflammation. The mechanism of colitis-induced hepcidin upregulation involves both BMP6 and IL-6.
Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.
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19 MeSH Terms
Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism.
Yu PB, Hong CC, Sachidanandan C, Babitt JL, Deng DY, Hoyng SA, Lin HY, Bloch KD, Peterson RT
(2008) Nat Chem Biol 4: 33-41
MeSH Terms: Animals, Antimicrobial Cationic Peptides, Bone Morphogenetic Protein Receptors, Type I, Bone Morphogenetic Proteins, Cell Differentiation, Cell Line, Tumor, Hepcidins, Iron, Mice, Mice, Inbred C57BL, Osteoblasts, Osteogenesis, Phosphorylation, Pyrazoles, Pyrimidines, Signal Transduction, Smad Proteins, Small Molecule Libraries, Transcription, Genetic, Zebrafish
Show Abstract · Added August 19, 2012
Bone morphogenetic protein (BMP) signals coordinate developmental patterning and have essential physiological roles in mature organisms. Here we describe the first known small-molecule inhibitor of BMP signaling-dorsomorphin, which we identified in a screen for compounds that perturb dorsoventral axis formation in zebrafish. We found that dorsomorphin selectively inhibits the BMP type I receptors ALK2, ALK3 and ALK6 and thus blocks BMP-mediated SMAD1/5/8 phosphorylation, target gene transcription and osteogenic differentiation. Using dorsomorphin, we examined the role of BMP signaling in iron homeostasis. In vitro, dorsomorphin inhibited BMP-, hemojuvelin- and interleukin 6-stimulated expression of the systemic iron regulator hepcidin, which suggests that BMP receptors regulate hepcidin induction by all of these stimuli. In vivo, systemic challenge with iron rapidly induced SMAD1/5/8 phosphorylation and hepcidin expression in the liver, whereas treatment with dorsomorphin blocked SMAD1/5/8 phosphorylation, normalized hepcidin expression and increased serum iron levels. These findings suggest an essential physiological role for hepatic BMP signaling in iron-hepcidin homeostasis.
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20 MeSH Terms