scholarly journals Hereditary hemochromatosis promotes colitis and colon cancer and causes bacterial dysbiosis in mice

2020 ◽  
Vol 477 (19) ◽  
pp. 3867-3883 ◽  
Author(s):  
Sathish Sivaprakasam ◽  
Bojana Ristic ◽  
Nithya Mudaliar ◽  
Abdul N. Hamood ◽  
Jane Colmer-Hamood ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Iron Overload ◽  
Genetic Disorder ◽  
Hereditary Hemochromatosis ◽  
Wild Type Mouse ◽  
Wild Type ◽  
Impaired Wound Healing ◽  
Excess Iron ◽  
Mouse Colon ◽  
16S Rna

Hereditary hemochromatosis (HH), an iron-overload disease, is a prevalent genetic disorder. As excess iron causes a multitude of metabolic disturbances, we postulated that iron overload in HH disrupts colonic homeostasis and colon–microbiome interaction and exacerbates the development and progression of colonic inflammation and colon cancer. To test this hypothesis, we examined the progression and severity of colitis and colon cancer in a mouse model of HH (Hfe−/−), and evaluated the potential contributing factors. We found that experimentally induced colitis and colon cancer progressed more robustly in Hfe−/− mice than in wild-type mice. The underlying causes were multifactorial. Hfe−/− colons were leakier with lower proliferation capacity of crypt cells, which impaired wound healing and amplified inflammation-driven tissue injury. The host/microflora axis was also disrupted. Sequencing of fecal 16S RNA revealed profound changes in the colonic microbiome in Hfe−/− mice in favor of the pathogenic bacteria belonging to phyla Proteobacteria and TM7. There was an increased number of bacteria adhered onto the mucosal surface of the colonic epithelium in Hfe−/− mice than in wild-type mice. Furthermore, the expression of innate antimicrobial peptides, the first-line of defense against bacteria, was lower in Hfe−/− mouse colon than in wild-type mouse colon; the release of pro-inflammatory cytokines upon inflammatory stimuli was also greater in Hfe−/− mouse colon than in wild-type mouse colon. These data provide evidence that excess iron accumulation in colonic tissue as happens in HH promotes colitis and colon cancer, accompanied with bacterial dysbiosis and loss of function of the intestinal/colonic barrier.

scholarly journals Iron age: novel targets for iron overload

Hematology ◽  
2014 ◽  
Vol 2014 (1) ◽  
pp. 216-221 ◽  
Author(s):  
Carla Casu ◽  
Stefano Rivella
Keyword(s):  
Iron Overload ◽  
Iron Age ◽  
Iron Metabolism ◽  
Iron Absorption ◽  
Hereditary Hemochromatosis ◽  
Therapeutic Approaches ◽  
Hepcidin Expression ◽  
Beneficial Effects ◽  
Excess Iron ◽  
Major Factors

Abstract Excess iron deposition in vital organs is the main cause of morbidity and mortality in patients affected by β-thalassemia and hereditary hemochromatosis. In both disorders, inappropriately low levels of the liver hormone hepcidin are responsible for the increased iron absorption, leading to toxic iron accumulation in many organs. Several studies have shown that targeting iron absorption could be beneficial in reducing or preventing iron overload in these 2 disorders, with promising preclinical data. New approaches target Tmprss6, the main suppressor of hepcidin expression, or use minihepcidins, small peptide hepcidin agonists. Additional strategies in β-thalassemia are showing beneficial effects in ameliorating ineffective erythropoiesis and anemia. Due to the suppressive nature of the erythropoiesis on hepcidin expression, these approaches are also showing beneficial effects on iron metabolism. The goal of this review is to discuss the major factors controlling iron metabolism and erythropoiesis and to discuss potential novel therapeutic approaches to reduce or prevent iron overload in these 2 disorders and ameliorate anemia in β-thalassemia.

Target TMPRSS6 for the Treatment of Hereditary Hemochromatosis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1047-1047
Author(s):  
Sheri Booten ◽  
Daniel Knox ◽  
Luis Alvarado ◽  
Shuling Guo ◽  
Brett P. Monia
Keyword(s):  
Iron Overload ◽  
Genetic Disorder ◽  
Hereditary Hemochromatosis ◽  
Genetic Defect ◽  
Transferrin Saturation ◽  
Common Mutation ◽  
C282y Mutation ◽  
Iron Storage ◽  
Hepcidin Expression ◽  
Iron Deficient

Abstract Abstract 1047 Hereditary hemochromatosis (HH) is a genetic disorder in which hyperabsorption of dietary iron leads to accumulation of iron in multiple tissues including liver and heart. A common clinical manifestation in HH patients is cirrhosis and hepatocellular carcinoma as a result of iron-mediated injury in liver. The most prevalent genetic defect for HH is the failure to up-regulate hepcidin, a peptide hormone that inhibits the absorption of iron in duodenum and the release of iron from intracellular iron storage such as macrophages. Mutations in a number of genes have been identified as the cause for HH, including hepcidin itself. However, the most common mutation is C282Y mutation in HFE, which is a positive regulator for hepcidin expression. C282Y mutation represents about 85% of the HH population. HFE C282Y HH is an autosomal recessive disease with a ∼50% penetrance. Currently, the only treatment available for iron overload is phlebotomy which will continue throughout the patient's life. Hepcidin is mainly expressed and secreted by the liver and its expression is regulated predominantly at the transcription level. TMPRSS6, a transmembrane serine protease mutated in iron-refractory, iron-deficient anemia, is a major suppressor for hepcidin expression. It's been demonstrated that hepcidin expression is significantly elevated in Tmprss6−/− mice and reduction of TMPRSS6 in Hfe−/− mice could ameliorate the iron overload phenotype (Du et al. Science 2008; Folgueras et al. Blood 2008; Finberg KE et al., Blood, 2011). Using second generation antisense technology, we identified antisense oligonucleotides (ASOs) targeting mouse TMPRSS6 for the treatment of HH. These compounds were first identified through in vitro screens in mouse primary hepatocytes. After 4 weeks of treatment in C57BL/6 mice on normal chow, we observed an 80% to 90% reduction of liver TMPRSS6 mRNA with a subsequent 2–3 fold induction of liver hepcidin mRNA. Serum iron and transferrin saturation levels were reduced by ∼50%. These ASOs are currently being evaluated in a diet-induced iron overload model and an Hfe−/− iron overload model. Our preliminary results demonstrate that targeting TMPRSS6 is a viable approach for the treatment of hereditary hemochromatosis and possibly other iron-loading diseases associated with suppressed hepcidin levels. Disclosures: Booten: Isis Pharmaceuticals: Employment. Knox:Isis Pharmaceuticals: Summer Intern. Alvarado:Isis Pharmaceuticals: Employment. Guo:Isis Pharmaceuticals: Employment. Monia:Isis Pharmaceuticals: Employment.

scholarly journals Hemochromatosis - modern condition of the problem

2018 ◽  
Vol 90 (3) ◽  
pp. 107-112
Author(s):  
N B Voloshina ◽  
M F Osipenko ◽  
N V Litvinova ◽  
A N Voloshin
Keyword(s):  
Hepatocellular Carcinoma ◽  
Iron Overload ◽  
Therapeutic Intervention ◽  
Clinical Observation ◽  
Genetic Disorder ◽  
Hereditary Hemochromatosis ◽  
Hereditary Factors ◽  
Life Threatening ◽  
Common Genetic Disorder ◽  
Modern Condition

The iron overload syndrome can be associated with various acquired states and hereditary factors. Hereditary hemochromatosis is the most common genetic disorder. Without therapeutic intervention the disease can lead to the development of life-threatening complications such as cirrhosis, hepatocellular carcinoma. The article presents data on pathogenesis, diagnosis and treatment of hereditary hemochromatosis. Own clinical observation is given.

HAMP and HVJ as Candidate Modifier Genes in Type1 Hereditary Hemochromatosis with High Iron Burden and in Porphyria Cutanea Tarda (PCT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1544-1544
Author(s):  
Richard S. Ajioka ◽  
John D. Phillips ◽  
Robert B. Weiss ◽  
Diane M. Dunn ◽  
James P. Kushner
Keyword(s):  
Iron Overload ◽  
Splice Site ◽  
Hereditary Hemochromatosis ◽  
Modifier Genes ◽  
Hepatic Iron ◽  
Iron Loading ◽  
Wild Type ◽  
Hepatic Iron Overload ◽  
Number Of Patients

Abstract Homozygosity for the HFE C282Y mutation accounts for approximately 90 percent of HFE-associated (type 1) hereditary hemochromatosis. The clinical phenotype in C282Y homozygotes, however, ranges from simply an elevated percent saturation of transferrin to organ damage due to iron overload. Modifier genes have been proposed to explain this phenotypic variability. Hepatic siderosis is a nearly constant finding in patients with PCT. Approximately 20 percent of patients with PCT are homozygotes for the C282Y HFE mutation but the cause of hepatic iron loading in the remaining 80 percent is not known. Approximately one-third of patients with PCT are heterozygotes for mutations of the uroporphyrinogen decarboxylase (URO-D) gene (familial PCT) but pedigree studies indicate that clinical expression occurs only in those URO-D heterozygotes who develop hepatic siderosis. Most patients with PCT have no URO-D mutations (sporadic PCT) but virtually all sporadic cases have hepatic iron overload. Two genes known to affect iron homeostasis are hepcidin (HAMP) and hemojuvelin (HJV). Heterozygosity for HAMP and HJV mutations have been associated with marked iron overload in a small number of patients with type 1 hemochromatosis (Blood.2004; 103:2835–40; Blood Cells Mol Dis.2004; 33:338–43). We asked if mutations of HAMP or HJV could account for hepatic iron overload in highly penetrant C282Y homozygotes and in PCT patients with or without HFE mutations. We sequenced the HAMP and HJV genes in 96 hemochromatosis patients with grade 3–4 (scale 0–4) hepatic parenchymal cell stainable iron (HPCSI) and 96 PCT patients with variable degrees of hepatic siderosis. Ninety-four percent (90) of the hemochromatosis patients were C282Y homozygotes, 4.2 percent (4) were C282Y heterozygotes and 2.1 percent (2) were wild type 282 homozygotes. No exonic changes or splice site mutations were detected in either the HAMP or HJV genes. Eighty-three of the 96 PCT patients were genotyped at the HFE locus. Twenty-five percent (21) were C282Y homozygotes, 23 percent (19) were C282Y heterozygotes and 52 percent (43) were wild type 282 homozygotes. No exonic changes or splice site mutations were detected in the HJV gene of patients with PCT but two PCT patients were found to be heterozygotes for HAMP mutations. The first had the previously identified 212G→A transition leading to a G71D substitution. The second had a 248A→C transversion corresponding to K83R in the peptide. Both of these PCT patients were HFE 282 wild type homozygotes but both had grade 4 HPCSI. These data indicate that heterozygosity for mutations of HAMP or HJV rarely modifies the iron loading phenotype in either type 1 hemochromatosis or PCT. Other modifier loci must exist.

Design of an Ongoing Phase I/II Open-Label, Dose-Escalation Trial Using the Oral Chelator Deferasirox To Treat Iron Overload in HFE-Related Hereditary Hemochromatosis (HH).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2680-2680 ◽  
Author(s):  
A. Pietrangelo ◽  
P. Brissot ◽  
H. Bonkovsky ◽  
C. Niederau ◽  
L. Rojkjaer ◽  
...  
Keyword(s):  
Iron Overload ◽  
Dose Escalation ◽  
Genetic Disorder ◽  
Hereditary Hemochromatosis ◽  
Transferrin Saturation ◽  
Analysis Of Covariance ◽  
Dose Escalation Study ◽  
True Incidence ◽  
Medical Disorders ◽  
Alternative Treatment Option

Abstract HH is a genetic disorder commonly associated with homozygosity for the C282Y HFE mutation and characterized by progressive iron overload through increased intestinal absorption. Organ failure due to iron toxicity may develop. Iron removal by phlebotomy is the preferred treatment and has been demonstrated to prevent or reverse some of the complications of iron overload. However, compliance with a weekly phlebotomy schedule is variable, and some patients are ineligible for phlebotomy due to underlying medical disorders. Thus, if an oral iron chelator such as deferasirox proves to be safe and effective, HH patients will have an alternative treatment option. This is an inter-patient dose-escalation study of deferasirox (5, 10, 15, 20 mg/kg) given daily for 24 weeks to C282Y homozygous HH patients with a pre-treatment serum ferritin (SF) value ≥300 μg/L and ≤2000 μg/L, and transferrin saturation ≥45%. Major exclusion criteria are men with hemoglobin <13 g/dL, women with hemoglobin <12 g/dL, a history of blood transfusion during 6 months prior to study entry, serum creatinine above the upper limit of normal (ULN), and serum ALT ≥2xULN at screening. The primary endpoint is the incidence and severity of adverse events (AEs). Secondary endpoints include the change in SF from baseline at 24 weeks, the time to normalization of SF (defined as the first occurrence of reduction of SF to <100 μg/L), the longitudinal course of SF, and the pharmacokinetics of deferasirox. It is estimated that at least 40 patients are needed to evaluate safety at all dose levels. Cohorts of 8 patients per dose level will be used in order to detect AEs with a 25% true incidence rate at that dose with 90% power. Safety monitoring will be based on medical review and a 2-parameter Bayesian logistic regression model for dose-dependent probabilities of a severe AE. To assess efficacy, the change from baseline in SF after 24 weeks of treatment will be analyzed by performing an analysis of covariance (ANCOVA). To date, 11 patients (9 men, 2 women; all Caucasian; mean age 56 years) with a mean of 7 years since HH diagnosis have been treated at 5 mg/kg/day for at least 4 weeks. There was a mean of 7 years since HH diagnosis, with 2 patients not having been previously treated. The remaining 9 had been treated with phlebotomy, one of whom had also been treated with deferoxamine. Baseline iron studies and ALT values for the 11 patients treated at 5 mg/kg/day are summarized in the table. The dose of deferasirox has been escalated to 10 mg/kg/day after no patients were seen to experience severe AEs at 5 mg/kg/day. In conclusion, this ongoing study will generate preliminary safety and efficacy data for deferasirox use in iron-overloaded HH patients, indicating whether deferasirox could be an alternative to phlebotomy in selected patients. Parameter n Mean±SD Median Range Normal range SF, ng/mL 11 633.0±428.9 567.0 350–1880 30–400 (men); 15–150 (women) Transferrin saturation, % 11 75.5±19.6 82.0 39–95 20–55 ALT, U/L 11 43.4±33.4 34.0 8–122 0–45

International Comparison Study of Toxic Iron Assays in Patients with Iron Overload Disorders

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4033-4033
Author(s):  
Louise De Swart ◽  
Jan C.M. Hendriks ◽  
Lisa Van der Vorm ◽  
Ioav Z. Cabantchik ◽  
Patricia J. Evans ◽  
...  
Keyword(s):  
Iron Overload ◽  
Research Funding ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Transferrin Saturation ◽  
Iron Chelation ◽  
Thalassemia Major ◽  
The Other ◽  
Serum Samples ◽  
Excess Iron

Abstract Background: Imbalances in iron homeostasis result in a variety of disorders. Excess iron accumulates in the circulation and tissues of patients with hereditary hemochromatosis (HH), iron-loading anemia (β-thalassemia major and intermedia (Thal), myelodysplastic syndromes (MDS) and sickle cell disease after transfusion (SCD). To prevent iron-induced tissue damage, detection of impending iron toxicity is needed before complications develop and become irreversible. Plasma non-transferrin bound iron (NTBI) and its labile (redox active) component (LPI) are thought to be potentially toxic forms of iron identified in the serum of patients with iron overload. Objective: To increase our insights into NTBI and LPI concentrations measured by the current worldwide leading analytical assays in four different categories of iron overloaded patients (HH, Thal, MDS, transfused SCD) undergoing various treatments (phlebotomies, iron chelation, red blood cell transfusions). Methods: We compared 10 different assays (5 NTBI, 1 NTBI isoform specific and 4 LPI) as part of an international inter-laboratory study. Serum samples were from 60 patients with 4 iron overload disorders. Serum samples were split into two aliquots, coded (blinded), stored at -80°C and shipped for analysis to 5 different laboratories worldwide. Laboratories performed duplicate measurements on each aliquot of a serum sample on 2 different days, resulting in a total of 4 measurements for each sample. Some laboratories provided multiple assays. Results: NTBI and LPI measurements in the serum of iron-overloaded patients showed good reproducibility with a high between-sample (range 67.1-97.2%) and a low within-sample variance (0-2.2%) relative to the total variance of each assay. Absolute NTBI and LPI levels differed considerably between assays. Four assays (2 LPI and 2 NTBI) also reported negative values. LPI levels were ± 10% of the NTBI levels. Highest levels were observed in patients with naive HH and naive Thal intermedia, transfusion-dependent MDS and transfusion-dependent Thal major. These 4 patients groups also had the highest transferrin saturation (TSAT) levels, but only 3 of them were among the groups with the highest ferritin levels. Eight (4 LPI and 4 NTBI) of the 10 assays could discriminate well between iron overload diseases. In general correlations were highest within the same group of NTBI or LPI assays. Interestingly, one of the LPI assays showed better correlations with NTBI assays (range rs=0.85-0.90) than with the other LPI assays (range rs=0.61-0.77). In contrast, one of the NTBI assays showed better correlations with LPI assays (range rs=0.67-0.75) than with the other NTBI assays (range rs=0.50-0.59). The assays show a hyperbolic relation with TSAT; NTBI and LPI concentrations only substantially increase above a certain TSAT level of ~70% and ~ 90%, respectively. This is illustrated for both a representative NTBI (Figure 1A) and LPI assay (Figure 1B). This relation does not exist between any of the assays and ferritin (Figure 1C,D). Conclusions: While NTBI and LPI values of various assays are well correlated and discriminate between iron overload disorders, absolute values differed considerably between assays. Both standardization of assays and clinical outcome studies to determine clinically relevant toxic thresholds are needed. At present TSAT may provide a useful alternative in the clinical management of patients with iron overload. Figure 1: Relation between representative assays and TSAT, Ferritin. Assay results are given for day 2 as duplicate measurements (circle and square). Figure 1:. Relation between representative assays and TSAT, Ferritin. Assay results are given for day 2 as duplicate measurements (circle and square). Disclosures De Swart: Novartis Europe: Research Funding. Swinkels:Novartis Europe: Research Funding.

BMP/Smad signaling is not enhanced in Hfe-deficient mice despite increased Bmp6 expression

Blood ◽  
2009 ◽  
Vol 114 (12) ◽  
pp. 2515-2520 ◽  
Author(s):  
Léon Kautz ◽  
Delphine Meynard ◽  
Céline Besson-Fournier ◽  
Valérie Darnaud ◽  
Talal Al Saati ◽  
...  
Keyword(s):  
Iron Overload ◽  
Hereditary Hemochromatosis ◽  
Bmp Signaling ◽  
Signaling Cascade ◽  
Mrna Levels ◽  
Wild Type ◽  
Smad Signaling ◽  
Hepcidin Expression ◽  
Hepcidin Mrna ◽  
Deficient Mice

Abstract Impaired regulation of hepcidin expression in response to iron loading appears to be the pathogenic mechanism for hereditary hemochromatosis. Iron normally induces expression of the BMP6 ligand, which, in turn, activates the BMP/Smad signaling cascade directing hepcidin expression. The molecular function of the HFE protein, involved in the most common form of hereditary hemochromatosis, is still unknown. We have used Hfe-deficient mice of different genetic backgrounds to test whether HFE has a role in the signaling cascade induced by BMP6. At 7 weeks of age, these mice have accumulated iron in their liver and have increased Bmp6 mRNA and protein. However, in contrast to mice with secondary iron overload, levels of phosphorylated Smads 1/5/8 and of Id1 mRNA, both indicators of BMP signaling, are not significantly higher in the liver of these mice than in wild-type livers. As a consequence, hepcidin mRNA levels in Hfe-deficient mice are similar or marginally reduced, compared with 7-week-old wild-type mice. The inappropriately low levels of Id1 and hepcidin mRNA observed at weaning further suggest that Hfe deficiency triggers iron overload by impairing hepatic Bmp/Smad signaling. HFE therefore appears to facilitate signal transduction induced by the BMP6 ligand.

scholarly journals Role of Exosomes in Hepcidin Regulation in β-Thalassemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 954-954
Author(s):  
Marc Ruiz Martinez ◽  
Melanie Castro-Mollo ◽  
Navneet Dogra ◽  
Wenbin An ◽  
Ester Borroni ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Iron Overload ◽  
Iron Metabolism ◽  
Wild Type Mouse ◽  
Negative Regulator ◽  
Mouse Serum ◽  
Wild Type ◽  
Ineffective Erythropoiesis ◽  
Thalassemic Patient ◽  
Hepcidin Expression

β-thalassemia is characterized by ineffective erythropoiesis and iron overload. Ineffective erythropoiesis causes iron overload by suppressing hepcidin, the main negative regulator of iron absorption and recycling, and is mediated by secretion of erythroferrone from bone marrow cells. Targeted treatment for ineffective erythropoiesis is unavailable. Furthermore, molecular mechanisms involved in ineffective erythropoiesis and the details of how erythropoiesis regulates iron metabolism are incompletely understood. Lastly, while loss of erythroferrone in β-thalassemic mice leads to partial reversal of iron overload [Kautz Blood 2015], erythroferrone ablated mice are still able to suppress hepcidin after phlebotomy [Kautz Nat Med 2014]. These finding provide evidence of additional regulatory crosstalk between erythropoiesis and iron metabolism. We hypothesize that bone-marrow derived exosomes regulate iron metabolism by modulating hepcidin. Exosomes are small extracellular vesicles derived from multi-vesicular bodies forming intraluminal vesicles which fuse with the plasma membrane and are released by many different cell types [Thery Nat Rev Immun 2002]. In light of their capacity for cell-cell communication and modification of the microenvironment, exosomes have been widely studied in multiple diseases [Valadi Nat Cell Bio 2007] despite which, erythropoiesis-derived exosomes and their role in iron metabolism regulation remain unexplored. Our preliminary data demonstrate that phlebotomy in wild type mice results in increased exosome concentration in serum and that exosomes are increased in th3/+ mouse serum (Figure 1a). Furthermore, hepcidin induction by exosome depleted-FBS is decreased relative to FBS (Figure 1b), and exosomes isolated from FBS induce hepcidin in a dose response manner in vitro (Figure 1c). We thus propose to explore the mechanistic relationship between exosomes and hepcidin regulation in β-thalassemia. Serum samples from patients with β-thalassemia major and age / gender matched controls were collected; all patients were treated with iron chelation therapy and all samples were collected immediately prior to transfusion. Exosome fractions were purified and analyzed in patients relative to controls. Although there is no difference in the number of exosomes or mean particle size within the exosomal fraction, exosomal protein content per volume of serum is significantly decreased in patients relative to controls. In addition, the treatment of primary wild type mouse hepatocytes with sera from patients and controls reveals the expected relatively decreased hepcidin induction in β-thalassemic patient sera treated hepatocytes relative to control sera; a similar difference is seen in hepatocytes treated with exosome-depleted sera from patients and controls (Figure 2a). These findings suggest that hepcidin suppression is a consequence of the exosome-free portion of serum from control and β-thalassemic samples. Furthermore, only exosomes derived from β-thalassemic patient sera induces hepcidin expression in primary wild type mouse hepatocyte cultures (Figure 2b). Lastly, exosomes derived from β-thalassemic patient sera do not affect ERK1/2 and STAT3 signaling in primary hepatocytes but increase SMAD1/5/8 (Figure 2c) and decrease AKT signaling (Figure 2d). Taken together, these findings demonstrate that exosomes enhance hepcidin expression via increased SMAD1/5/8 signaling, that increased hepcidin may influence multiple signaling pathways by an autocrine mechanism in response to exosomes, and that exosomes counterbalance hepcidin suppressive substances in the exosome-depleted serum from β-thalassemic samples. Our studies provide novel insights into the important previously unexplored mechanism of hepcidin regulation by exosomes in both physiologic and pathologic states. Disclosures Coates: apo pharma: Consultancy, Honoraria, Speakers Bureau; vifor: Consultancy, Honoraria; celgene: Consultancy, Honoraria, Other: steering committee of clinical study; agios pharma: Consultancy, Honoraria. Ginzburg:La Jolla Pharma: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Neutrophils from hereditary hemochromatosis patients are protected from iron excess and are primed

2020 ◽  
Vol 4 (16) ◽  
pp. 3853-3863
Author(s):  
Cyril Renassia ◽  
Sabine Louis ◽  
Sylvain Cuvellier ◽  
Nadia Boussetta ◽  
Jean-Christophe Deschemin ◽  
...  
Keyword(s):  
Iron Overload ◽  
Mouse Models ◽  
Oxidative Burst ◽  
Iron Homeostasis ◽  
Genetic Disorder ◽  
Hereditary Hemochromatosis ◽  
Neutrophil Function ◽  
Intracellular Iron ◽  
Hepcidin Expression ◽  
Neutrophil Priming

Abstract Iron is required for the oxidative response of neutrophils to allow the production of reactive oxygen species (ROS). However, neutrophil function may be severely altered in conditions of iron overload, as observed in chronically transfused patients. Therefore, a tight regulation of neutrophil iron homeostasis seems to be critical for avoiding iron toxicity. Hepcidin is the key iron regulator in organisms; however, no studies have investigated its role in maintaining neutrophil iron homeostasis or characterized neutrophil function in patients with hereditary hemochromatosis (HH), a common iron overload genetic disorder that results from a defect in hepcidin production. To explore these issues, we studied 2 mouse models of iron overload: an experimentally induced iron overload model (EIO), in which hepcidin is increased, and a genetic HH model of iron overload with a deletion of hepatic hepcidin. We found that iron-dependent increase of hepatic hepcidin results in neutrophil intracellular iron trapping and consecutive defects in oxidative burst activity. In contrast, in both HH mouse models and HH patients, the lack of hepcidin expression protects neutrophils from toxic iron accumulation. Moreover, systemic iron overload correlated with a surprising neutrophil priming and resulted in a more powerful oxidative burst. Indeed, important factors in neutrophil priming and activation, such as tumor necrosis factor α (TNF-α), VCAM-1, and ICAM-1 are increased in the plasma of HH patients and are associated with an increase in HH neutrophil phagocytosis capacity and a decrease in L-selectin surface expression. This is the first study to characterize neutrophil iron homeostasis and associated functions in patients with HH.

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