Hepcidin and Host Defense against Infectious Diseases.

Hepcidin is the master regulator of iron homeostasis in vertebrates. The synthesis of hepcidin is induced by systemic iron levels and by inflammatory stimuli. While the role of hepcidin in iron regulation is well established, its contribution to host defense is emerging as complex and multifaceted. In this review, we summarize the literature on the role of hepcidin as a mediator of antimicrobial immunity. Hepcidin induction during infection causes depletion of extracellular iron, which is thought to be a general defense mechanism against many infections by withholding iron from invading pathogens. Conversely, by promoting iron sequestration in macrophages, hepcidin may be detrimental to cellular defense against certain intracellular infections, although critical in vivo studies are needed to confirm this concept. It is not yet clear whether hepcidin exerts any iron-independent effects on host defenses

Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload

Iron overload is the hallmark of hereditary hemochromatosis and a complication of iron-loading anemias such as β-thalassemia. Treatment can be burdensome and have significant side effects, and new therapeutic options are needed. Iron overload in hereditary hemochromatosis and β-thalassemia intermedia is caused by hepcidin deficiency. Although transgenic hepcidin replacement in mouse models of these diseases prevents iron overload or decreases its potential toxicity, natural hepcidin is prohibitively expensive for human application and has unfavorable pharmacologic properties. Here, we report the rational design of hepcidin agonists based on the mutagenesis of hepcidin and the hepcidin-binding region of ferroportin and computer modeling of their docking. We identified specific hydrophobic/aromatic residues required for hepcidin-ferroportin binding and obtained evidence in vitro that a thiol-disulfide interaction between ferroportin C326 and the hepcidin disulfide cage may stabilize binding. Guided by this model, we showed that 7–9 N-terminal amino acids of hepcidin, including a single thiol cysteine, comprised the minimal structure that retained hepcidin activity, as shown by the induction of ferroportin degradation in reporter cells. Further modifications to increase resistance to proteolysis and oral bioavailability yielded minihepcidins that, after parenteral or oral administration to mice, lowered serum iron levels comparably to those after parenteral native hepcidin. Moreover, liver iron concentrations were lower in mice chronically treated with minihepcidins than those in mice treated with solvent alone. Minihepcidins may be useful for the treatment of iron overload disorders

Early postnatal hypoferremia in low birthweight and preterm babies: A prospective cohort study in hospital-delivered Gambian neonates.

BACKGROUND: Neonates, particularly those born preterm (PTB) and with low birthweight (LBW), are especially susceptible to bacterial and fungal infections that cause an estimated 225,000 deaths annually. Iron is a vital nutrient for the most common organisms causing septicaemia. Full-term babies elicit an immediate postnatal hypoferremia assumed to have evolved as an innate defence. We tested whether PTB and LBW babies are capable of the same response. METHODS: We conducted an observational study of 152 babies who were either PTB (born ≥32 to <37 weeks gestational age) and/or LBW (<2500 g) (PTB/LBW) and 278 term, normal-weight babies (FTB/NBW). Blood was sampled from the umbilical cord vein and artery, and matched venous blood samples were taken from all neonates between 6-24 h after delivery. We measured haematological, iron and inflammatory markers. FINDINGS: In both PTB/LBW and FTB/NBW babies, serum iron decreased 3-fold within 12 h of delivery compared to umbilical blood (7·5 ± 4·5 vs 23·3 ± 7·1 ng/ml, P < 0·001, n = 425). Transferrin saturation showed a similar decline with a consequent increase in unsaturated iron-binding capacity. C-reactive protein levels increased over 10-fold (P < 0·001) and hepcidin levels doubled (P < 0·001). There was no difference in any of these responses between PTB/LBW and FTB/NBW babies. INTERPRETATION: Premature or low birthweight babies are able to mount a very rapid hypoferremia that is indistinguishable from that in normal term babies. The data suggest that this is a hepcidin-mediated response triggered by acute inflammation at birth, and likely to have evolved as an innate immune response against bacterial and fungal septicaemia. TRIAL REGISTRATION: clinicaltrials.gov (NCT03353051). Registration date: November 27, 2017. FUNDING: Bill & Melinda Gates Foundation (OPP1152353)

Iron Homeostasis during Cystic Fibrosis Pulmonary Exacerbation

BACKGROUND: Hypoferremia is a marker of disease severity in cystic fibrosis (CF). The effect of systemic antibiotics on iron homeostasis during CF pulmonary exacerbation (CFPE) is unknown. Our central hypotheses were that, by the completion of treatment, serum iron would increase, serum concentrations of interleukin-6 (IL-6) and hepcidin-25, two mediators of hypoferremia, would decrease, and sputum iron would decrease. METHODS: Blood and sputum samples were collected from 12 subjects with moderate-to-severe CF (median percentage-predicted forced expiratory volume in 1 second (FEV(1) %) = 29%; median weight = 56 kg) within 24 hours of starting and completing a course of systemic antibiotics. RESULTS: After treatment, subjects showed median FEV(1) % and body weight improvements of 4.5% and 2.0 kg, respectively (p \u3c 0.05). Median serum iron rose by 2.4 μmol/L (p \u3c 0.05), but 75% of patients remained hypoferremic. Median serum IL-6 and hepcidin-25 levels fell by 12.1 pg/mL and 37.5 ng/mL, respectively (p \u3c 0.05). Median serum erythropoietin (EPO) and hemoglobin levels were unaffected by treatment. We observed a trend toward lower sputum iron content after treatment. CONCLUSIONS: Hypoferremia is a salient characteristic of CFPE that improves with waning inflammation. Despite antibiotic treatment, many patients remain hypoferremic and anemic because of ineffective erythropoiesis

Prenatal Inflammation-Induced Hypoferremia Alters Dopamine Function in the Adult Offspring in Rat: Relevance for Schizophrenia

Maternal infection during pregnancy has been associated with increased incidence of schizophrenia in the adult offspring. Mechanistically, this has been partially attributed to neurodevelopmental disruption of the dopamine neurons, as a consequence of exacerbated maternal immunity. In the present study we sought to target hypoferremia, a cytokine-induced reduction of serum non-heme iron, which is common to all types of infections. Adequate iron supply to the fetus is fundamental for the development of the mesencephalic dopamine neurons and disruption of this following maternal infection can affect the offspring's dopamine function. Using a rat model of localized injury induced by turpentine, which triggers the innate immune response and inflammation, we investigated the effects of maternal iron supplementation on the offspring's dopamine function by assessing behavioral responses to acute and repeated administration of the dopamine indirect agonist, amphetamine. In addition we measured protein levels of tyrosine hydroxylase, and tissue levels of dopamine and its metabolites, in ventral tegmental area, susbtantia nigra, nucleus accumbens, dorsal striatum and medial prefrontal cortex. Offspring of turpentine-treated mothers exhibited greater responses to a single amphetamine injection and enhanced behavioral sensitization following repeated exposure to this drug, when compared to control offspring. These behavioral changes were accompanied by increased baseline levels of tyrosine hydroxylase, dopamine and its metabolites, selectively in the nucleus accumbens. Both, the behavioral and neurochemical changes were prevented by maternal iron supplementation. Localized prenatal inflammation induced a deregulation in iron homeostasis, which resulted in fundamental alterations in dopamine function and behavioral alterations in the adult offspring. These changes are characteristic of schizophrenia symptoms in humans

Parasites, Porotic Hyperostosis, and the Implications of Changing Perspectives

Cribra orbitalia and porotic hyperostosis traditionally have been viewed (at least by archaeologists) as indicators of chronic iron deficiency anemia resulting from a dependency upon maize. Recent interpretations, however, have sought to explain these conditions as an evolutionary, adaptive response to intestinal parasites rather than as a consequence of poor nutrition. Thus diet is eliminated as a contributing factor. This model, however, adopts too simplistic a view of evolution. Furthermore, it concomitantly severs the well-documented link that exists between cranial lesions and cereal-based subsistence. A more realistic approach would be to incorporate both diet and pathogens (bacterial as well as parasitic) into a symbiotic model that acknowledges the important role of parasites in the etiology of cribra orbitalia and porotic hyperostosis, while maintaining the diagnostic value of these conditions as hallmarks of early agriculture

Modulation of iron metabolism in response to infection: Twists for all tastes

Iron is an essential nutrient for almost all living organisms, but is not easily made available. Hosts and pathogens engage in a fight for the metal during an infection, leading to major alterations in the host’s iron metabolism. Important pathological consequences can emerge from the mentioned interaction, including anemia. Several recent reports have highlighted the alterations in iron metabolism caused by different types of infection, and several possible therapeutic strategies emerge, based on the targeting of the host’s iron metabolism. Here, we review the most recent literature on iron metabolism alterations that are induced by infection, the consequent development of anemia, and the potential therapeutic approaches to modulate iron metabolism in order to correct iron-related pathologies and control the ongoing infection.This work is a result of the project Norte-01-0145-FEDER-000012-Structured program on bioengineered therapies for infectious diseases and tissue regeneration, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). This work was financed by FEDER-Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020-Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT-Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project PTDC/IMI-MIC/1683/2014 (POCI-01-0145-FEDER-016590). A.C.M. receives the individual fellowship SFRH/BPD/101405/2014 from FCT

Targeting the Hepcidin-Ferroportin Axis in the Diagnosis and Treatment of Anemias

The hepatic peptide hormone hepcidin regulates dietary iron absorption, plasma iron concentrations, and tissue iron distribution. Hepcidin acts by causing the degradation of its receptor, the cellular iron exporter ferroportin. The loss of ferroportin decreases iron flow into plasma from absorptive enterocytes, from macrophages that recycle the iron of senescent erythrocytes, and from hepatocytes that store iron, thereby lowering plasma iron concentrations. Malfunctions of the hepcidin-ferroportin axis contribute to the pathogenesis of different anemias. Deficient production of hepcidin causes systemic iron overload in iron-loading anemias such as beta-thalassemia; whereas hepcidin excess contributes to the development of anemia in inflammatory disorders and chronic kidney disease, and may cause erythropoietin resistance. The diagnosis of different forms of anemia will be facilitated by improved hepcidin assays, and the treatment will be enhanced by the development of hepcidin agonists and antagonists

Weight status and iron deficiency among urban Malian women of reproductive age

The present study investigated the association between weight status and Fe deficiency (ID) among urban Malian women of reproductive age. Height, weight, serum ferritin (SF), soluble transferrin receptor (sTfR) and C-reactive protein (CRP) concentrations were measured in sixty apparently healthy women aged 15-49 years old in Bamako, Mali. Prevalences of overweight and obese were 19 and 9%, respectively. SF was non-significantly different between overweight (84 mu g/l) and normal-weight women (52 mu g/l). The prevalence of ID (SF 8.3 mg/l) cases were recorded in the overweight and obese groups. The prevalence OR of ID (SF <12 mu g/l) in the overweight group was NS (OR = 0.3; P=0.363). Conversely, the chronic energy deficiency group was at a significantly higher risk of ID than the normal-weight group, adjusting or not for CRP (OR = 7.7; 95% CI 1.49, 39.96; P=0.015). The lack of association between overweight and ID in the present study could be due to the fact that the excess of body fat of the women might not be critical to induce chronic inflammation related to reduced Fe absorption. Future research based on a larger convenience sample should be designed to further investigate associations between overweight, obesity and ID in developing countries