Managing the Dual Nature of Iron to Preserve Health.

Because of its peculiar redox properties, iron is an essential element in living organisms, being involved in crucial biochemical processes such as oxygen transport, energy production, DNA metabolism, and many others. However, its propensity to accept or donate electrons makes it potentially highly toxic when present in excess and inadequately buffered, as it can generate reactive oxygen species. For this reason, several mechanisms evolved to prevent both iron overload and iron deficiency. At the cellular level, iron regulatory proteins, sensors of intracellular iron levels, and post-transcriptional modifications regulate the expression and translation of genes encoding proteins that modulate the uptake, storage, utilization, and export of iron. At the systemic level, the liver controls body iron levels by producing hepcidin, a peptide hormone that reduces the amount of iron entering the bloodstream by blocking the function of ferroportin, the sole iron exporter in mammals. The regulation of hepcidin occurs through the integration of multiple signals, primarily iron, inflammation and infection, and erythropoiesis. These signals modulate hepcidin levels by accessory proteins such as the hemochromatosis proteins hemojuvelin, HFE, and transferrin receptor 2, the serine protease TMPRSS6, the proinflammatory cytokine IL6, and the erythroid regulator Erythroferrone. The deregulation of the hepcidin/ferroportin axis is the central pathogenic mechanism of diseases characterized by iron overload, such as hemochromatosis and iron-loading anemias, or by iron deficiency, such as IRIDA and anemia of inflammation. Understanding the basic mechanisms involved in the regulation of hepcidin will help in identifying new therapeutic targets to treat these disorders.

Iron metabolism disorder regulated by BMP signaling in hypoxic pulmonary hypertension.

BACKGROUNDS AND AIMS: Unexplained iron deficiency is associated with poorer survival in patients with pulmonary hypertension (PH). Bone morphogenetic protein (BMP) signaling and BMP protein type II receptor (BMPR2) expression are important in the pathogenesis of PH. BMP6 in hepatocytes is a central transcriptional regulator of the iron hormone hepcidin that controls systemic iron balance. This study aimed to investigate the effects of BMP signaling on iron metabolism and its implication in hypoxia-induced PH. METHODS AND RESULTS: PH was induced in Sprague-Dawley Rats under hypoxia for 4 weeks. Compared with the control group, right ventricular systolic pressure and right ventricle hypertrophy index were both markedly increased, and serum iron level was significantly decreased with iron metabolic disorder in the hypoxia group. In cultured human pulmonary artery endothelial cells (HPAECs), hypoxia increased oxidative stress and apoptosis, which were reversed by supplementation with Fe agent. Meanwhile, iron chelator deferoxamine triggered oxidative stress and apoptosis in HPAECs, and treatment with antioxidant alleviated iron-deficiency-induced apoptosis by reducing reactive oxygen species production. Expression of hepcidin, BMP6 and hypoxia-inducible factor (HIF)-1α were significantly upregulated, while expression of BMPR2 was downregulated in hepatocytes in the hypoxia group, both in vivo and in vitro. Expression of hepcidin and HIF-1α were significantly increased by BMP6, while pretreatment with siRNA-BMPR2 augmented the enhanced expression of hepcidin and HIF-1α induced by BMP6. CONCLUSIONS: Iron deficiency promoted oxidative stress and apoptosis in HPAECs in hypoxia-induced PH, and enhanced expression of hepcidin regulated by BMP6/BMPR2 signaling may contribute to iron metabolic disorder.

The mutual crosstalk between iron and erythropoiesis.

Iron homeostasis and erythropoiesis are strongly interconnected. On one side iron is essential to terminal erythropoiesis for hemoglobin production, on the other erythropoiesis may increase iron absorption through the production of erythroferrone, the erythroid hormone that suppresses hepcidin expression Also erythropoietin production is modulated by iron through the iron regulatory proteins-iron responsive elements that control the hypoxia inducible factor 2-α. The second transferrin receptor, an iron sensor both in the liver and in erythroid cells modulates erythropoietin sensitivity and is a further link between hepcidin and erythropoiesis. When erythropoietin is decreased in iron deficiency the erythropoietin sensitivity is increased because the second transferrin receptor is removed from cell surface. A deranged balance between erythropoiesis and iron/hepcidin may lead to anemia, as in the case of iron deficiency, defective iron uptake and erythroid utilization or subnormal recycling. Defective control of hepcidin production may cause iron deficiency, as in the recessive disorder iron refractory iron deficiency anemia or in anemia of inflammation, or in iron loading anemias, which are characterized by excessive but ineffective erythropoiesis. The elucidation of the mechanisms that regulates iron homeostasis and erythropoiesis is leading to the development of drugs for the benefit of both iron and erythropoiesis disorders.

Abnormal whole-body energy metabolism in iron-deficient humans despite preserved skeletal muscle oxidative phosphorylation.

Iron deficiency impairs skeletal muscle metabolism. The underlying mechanisms are incompletely characterised, but animal and human experiments suggest the involvement of signalling pathways co-dependent upon oxygen and iron availability, including the pathway associated with hypoxia-inducible factor (HIF). We performed a prospective, case-control, clinical physiology study to explore the effects of iron deficiency on human metabolism, using exercise as a stressor. Thirteen iron-deficient (ID) individuals and thirteen iron-replete (IR) control participants each underwent 31P-magnetic resonance spectroscopy of exercising calf muscle to investigate differences in oxidative phosphorylation, followed by whole-body cardiopulmonary exercise testing. Thereafter, individuals were given an intravenous (IV) infusion, randomised to either iron or saline, and the assessments repeated ~ 1 week later. Neither baseline iron status nor IV iron significantly influenced high-energy phosphate metabolism. During submaximal cardiopulmonary exercise, the rate of decline in blood lactate concentration was diminished in the ID group (P = 0.005). Intravenous iron corrected this abnormality. Furthermore, IV iron increased lactate threshold during maximal cardiopulmonary exercise by ~ 10%, regardless of baseline iron status. These findings demonstrate abnormal whole-body energy metabolism in iron-deficient but otherwise healthy humans. Iron deficiency promotes a more glycolytic phenotype without having a detectable effect on mitochondrial bioenergetics.

Quantitative Proteome and Transcriptome Dynamics Analysis Reveals Iron Deficiency Response Networks and Signature in Neuronal Cells.

Iron and oxygen deficiencies are common features in pathophysiological conditions, such as ischemia, neurological diseases, and cancer. Cellular adaptive responses to such deficiencies include repression of mitochondrial respiration, promotion of angiogenesis, and cell cycle control. We applied a systematic proteomics analysis to determine the global proteomic changes caused by acute hypoxia and chronic and acute iron deficiency (ID) in hippocampal neuronal cells. Our analysis identified over 8600 proteins, revealing similar and differential effects of each treatment on activation and inhibition of pathways regulating neuronal development. In addition, comparative analysis of ID-induced proteomics changes in cultured cells and transcriptomic changes in the rat hippocampus identified common altered pathways, indicating specific neuronal effects. Transcription factor enrichment and correlation analysis identified key transcription factors that were activated in both cultured cells and tissue by iron deficiency, including those implicated in iron regulation, such as HIF1, NFY, and NRF1. We further identified MEF2 as a novel transcription factor whose activity was induced by ID in both HT22 proteome and rat hippocampal transcriptome, thus linking iron deficiency to MEF2-dependent cellular signaling pathways in neuronal development. Taken together, our study results identified diverse signaling networks that were differentially regulated by hypoxia and ID in neuronal cells.

Iron supplementation ameliorates aloin-induced iron deficiency anemia in rats.

Aloin, an anthraquinone glycoside, is one of other C-glycosides found in the leaf exudate of Aloe plant. Aloin possesses several biologic activities, including antitumor activity in vitro and in vivo. However, aloin treatment has shown iron deficiency anemia and erythropoiesis in vivo. The present study was undertaken to verify if iron supplementation could alleviate these perturbations, compared to doxorubicin, an anthracycline analog. Oral iron supplementation (20.56 mg elemental Fe/kg bw) to aloin-treated rats normalized red blood corpuscles count, hemoglobin concentration, and serum levels of total iron binding capacity and saturated transferrin, as well as hepatic iron content, hepcidin level, and mRNA expression of ferritin heavy chain (Ferr-H) and transferrin receptor-1 (TfR-1) genes. Although, serum hyperferremia, and leukocytosis were maintained, yet the spleen iron overload was substantially modulated. However, combined aloin and iron treatment increased iron storage levels in the heart and bone marrow, compared to aloin treatment per se. On other hand, oral iron supplementation to rats treated with doxorubicin (15 mg/kg bw) lessened the increase in the spleen iron content concomitantly with hepatic hepcidin level, rebound hepatic iron content to normal level, and by contrast augmented serum levels of iron and transferrin saturation. Also, activated Ferr-H mRNA expression and repressed TfR-1 mRNA expression were recorded, compared to doxorubicin treatment per se. Histopathological examination of the major body iron stores in rats supplemented with iron along with aloin or doxorubicin showed an increase in extramedullary hematopoiesis. In conclusion, iron supplementation restores the disturbances in iron homeostasis and erythropoiesis induced by aloin treatment.

Fermented goat's milk modulates immune response during iron deficiency anemia recovery.

BACKGROUND: Iron deficiency and iron overload can affect the normal functioning of the innate and adaptive immune responses. Fermented milk products may enhance immune functions, but little is known about the effect of fermented milks on modulation of the immune response during iron deficiency anemia and recovery with normal or high dietary iron intake. Eighty male Wistar rats were randomly assigned to a control group fed a standard diet or to an anemic group fed a diet deficit in iron. Control and anemic groups were fed for 30 days with diets based on a fermented goat's or cow's milk product, with normal iron content or iron overload. RESULTS: In general, during anemia recovery lectin and alternative complement pathway activity and lactoferrin decreased, because it improves iron homeostasis, which is critically important in immune system functions. Fermented goat's milk diet enhanced immune function during iron deficiency recovery, suppressed oxidant-induced eotaxin and fractalkine expression due to the concurrent reduction of free radical production and pro-inflammatory cytokines, and decreased monocyte chemoattractant protein-1 and monocyte migration and adhesion. The increase in interferon-γ can confer immunological colonization of gut microbiota and downregulate inflammation. CONCLUSION: Fermented goat's milk consumption enhances immune function, modifying complement pathway activity and decreasing pro-inflammatory cytokines as well as lactoferrin concentration, due to the improvement of iron homeostasis, which is critically important in the normal function of the immune system. © 2021 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Regulation of FGF23: Beyond Bone.

PURPOSE OF REVIEW: Fibroblast growth factor 23 (FGF23) is a bone- and bone marrow-derived hormone that is critical to maintain phosphate homeostasis. The principal actions of FGF23 are to reduce serum phosphate levels by decreasing kidney phosphate reabsorption and 1,25-dihydroxyvitamin D synthesis. FGF23 deficiency causes hyperphosphatemia and ectopic calcifications, while FGF23 excess causes hypophosphatemia and skeletal defects. Excess FGF23 also correlates with kidney disease, where it is associated with increased morbidity and mortality. Accordingly, FGF23 levels are tightly regulated, but the mechanisms remain incompletely understood. RECENT FINDINGS: In addition to bone mineral factors, additional factors including iron, erythropoietin, inflammation, energy, and metabolism regulate FGF23. All these factors affect Fgf23 expression, while some also regulate FGF23 protein cleavage. Conversely, FGF23 may have a functional role in regulating these biologic processes. Understanding the bi-directional relationship between FGF23 and non-bone mineral factors is providing new insights into FGF23 regulation and function.

Nutrition, Inflammation, and the Gut Microbiota among Outpatients with Active Tuberculosis Disease in India.

India has the highest rates of tuberculosis (TB) globally and a high prevalence of malnutrition; however, the interplay between host nutritional status, inflammation, and the gut microbiome in active tuberculosis disease (ATBD) is less well-studied. We examined differences in gut microbial composition and diversity based on undernutrition and inflammation status among outpatients with ATBD at the time of treatment initiation. During this exploratory cross-sectional study, outpatients (N = 32) with ATBD (confirmed by Xpert MTB/RIF) were enrolled in anti-TB treatment initiated at a hospital in rural southern India. The 16S rRNA sequencing was used to assess the composition of the gut microbiome. We assessed multiple markers of nutritional status, including micronutrient status concentrations (vitamin D [25(OH)D], vitamin B12, ferritin), anthropometry (body mass index, mid-upper arm circumference, and height), and C-reactive protein (CRP), as indicators of inflammation. We found that 25(OH)D was positively associated with the relative abundance of Oscillospira spp., a butyrate-producing genus linked with anti-inflammation effects, and that ferritin was positively associated with Proteobacteria taxa, which have been associated with worse inflammation in other studies. Finally, we found a greater abundance of inflammation-associated taxa from the Proteobacteria phylum and lower alpha-diversity indices among those who were underweight or who had low mid-upper arm circumference or short stature. In summary, we found differences in the gut microbiota composition and diversity among those with undernutrition compared with those with adequate nutrition status at the time of initiation of treatment among patients with ATBD in India. Clinical implications of these findings will need to be examined by larger longitudinal studies.

Complex Interactions in Regulation of Haematopoiesis-An Unexplored Iron Mine.

Iron is one of the most abundant metals on earth and is vital for the growth and survival of life forms. It is crucial for the functioning of plants and animals as it is an integral component of the photosynthetic apparatus and innumerable proteins and enzymes. It plays a pivotal role in haematopoiesis and affects the development and differentiation of different haematopoietic lineages, apart from its obvious necessity in erythropoiesis. A large amount of iron stores in humans is diverted towards the latter process, as iron is an indispensable component of haemoglobin. This review summarises the important players of iron metabolism and homeostasis that have been discovered in recent years and highlights the overall significance of iron in haematopoiesis. Its role in maintenance of haematopoietic stem cells, influence on differentiation of varied haematopoietic lineages and consequences of iron deficiency/overloading on development and maturation of different groups of haematopoietic cells have been discussed.

Iron metabolism in patients with rheumatoid arthritis.

OBJECTIVE: Anemia is the hematological issue that occurs most often as a manifestation in RA. The aim of the study was to assess iron deficiency in RA patients. PATIENTS AND METHODS: The study was carried out on 62 RA patients treated between 2016 and 2017. RESULTS: A higher percentage of RA patients compared to the control group had TSAT below 20% (43% vs. 5%), ferritin below the reference range (15% vs. 7%), sTfR above 1.59 mg/l (26% vs. 0%) and hepcidin below 14.5 ng/ml (56% vs. 2%). 60% of RA patients had iron deficiency, and 18% - anemia. Correlations were found between reduced levels of ferritin and patients being younger, female, with lower GGT and higher platelet counts. Correlations were also found between iron deficiency and patients being younger, female, having reduced hemoglobin, increased platelet counts, increased GFR, reduced GGT, lower disease activity, and less frequent use of sulfasalazine. CONCLUSIONS: Iron deficiency is common (64%) in RA patients where there is high disease activity. RA patients had lower transferrin, lower ferritin, lower hepcidin, and higher sTfR. Decreased DAS-28 and reduced hemoglobin were the strongest determinants of iron deficiency.

In Vivo Analysis of the Contribution of Proprotein Convertases to the Processing of FGF23.

Fibroblast growth factor 23 (FGF23) is a hormone secreted from fully differentiated osteoblasts and osteocytes that inhibits phosphate reabsorption by kidney proximal tubules. The full-length (i.e., intact) protein mediates FGF23 endocrine functions, while endoproteolytic cleavage at a consensus cleavage sequence for the proprotein convertases (PCs) inactivates FGF23. Two PCs, furin and PC5, were shown to cleave FGF23 in vitro at RHTR179↓, but whether they are fulfilling this function in vivo is currently unknown. To address this question, we used here mice lacking either or both furin and PC5 in cell-specific manners and mice lacking the paired basic amino acid-cleaving enzyme 4 (PACE4) in all cells. Our analysis shows that furin inactivation in osteoblasts and osteocytes results in a 25% increase in circulating intact FGF23, without any significant impact on serum phosphate levels, whether mice are maintained on a normal or a low phosphate diet. Under conditions of iron deficiency, FGF23 is normally processed in control mice, but its processing is impaired in mice lacking furin in osteoblasts and osteocytes. In contrast, FGF23 is normally cleaved following erythropoietin or IL-1ß injections in mice lacking furin or both furin and PC5, and in PACE4-deficient mice. Altogether, these studies suggest that furin is only partially responsible for FGF23 cleavage under certain conditions in vivo. The processing of FGF23 may therefore involve the redundant action of multiple PCs or of other peptidases in osteoblasts, osteocytes and hematopoietic cells.

Systemic iron deficiency does not affect the cardiac iron content and progression of heart failure.

Chronic heart failure (HF) is often accompanied by systemic iron deficiency (ID). However, effects of ID on cardiac iron status and progression of HF are unknown. To investigate these effects rats underwent LAD ligation to induce post-myocardial infarction HF or sham operation. After 3 weeks the animals from both groups were randomized into three subgroups: control, moderate ID and severe ID+anemia (IDA) by a combination of phlebotomy and low iron diet for 5 weeks. Serum and hepatic iron content were reduced by 55% and 70% (ID) and by 80% and 77% (IDA), respectively, while cardiac iron content was unchanged in HF rats. Changes in expression of all cardiomyocyte iron handling proteins indicating preserved cardiomyocytes iron status in HF and ID/IDA. Contractile function of LV cardiomyocytes, Ca2+ transient amplitude, sarcoplasmic reticulum Ca2+ release and SERCA2a function was augmented by ID and IDA and it was accompanied by an increase in serum catecholamines. Neither ID nor IDA affected left ventricular (LV) systolic or diastolic function or dimensions. To sum up, systemic ID does not result in cardiac ID and does not affect progression of HF and even improves contractile function and Ca2+ handling of isolated LV cardiomyocytes, however, at the cost of increased catecholamine level. This suggests that intravenous iron therapy should be considered as an additional therapeutic option in HF, preventing the increase of catecholaminergic drive with its well-known long-term adverse effects.

Alteration of iron (Fe), copper (Cu), zinc (Zn), and manganese (Mn) tissue levels and speciation in rats with desferioxamine-induced iron deficiency.

The objective of the present study was to investigate the impact of iron deficiency and iron replenishment on serum iron (Fe), copper (Cu), manganese (Mn), and zinc (Zn) speciation and tissue accumulation in a deferrioxamine-induced model of iron deficiency. A total of 26 male Wistar rats were divided into three groups: control; Fe-deficient; Fe-replenished (with iron (II) gluconate). Serum ferritin and transferrin levels were assessed using immunoturbudimetric method. Liver, spleen, and serum metal levels were assessed using ICP-MS. Speciation analysis was performed using a hyphenated HPLC-ICP-MS technique. Desferrioxamine injections resulted in a significant decrease in tissue iron content that was reversed by Fe supplementation. Iron speciation revealed a significant increase in serum transferrin-bound iron and reduced ferritin-bound Fe levels. Serum but not tissue Cu levels were characterized by a significant decrease in hypoferremic rats, whereas ceruloplasmin-bound fraction tended to increase. At the same time, Zn levels were found to be higher in liver, spleen, and serum of Fe-deficient rats with a predominant increase in low molecular weight fraction.Both iron-deficient and iron-replenished rats were characteirzed by increased transferrin-bound Mn levels and reduced low-molecular weight fraction. Hypothetically, these differences may be associated with impaired Fe metabolism under Fe-deficient conditions predisposing to impairment of essential metal handling. However, further studies aimed at assessment of the impact on Fe deficiency on metal metabolism are highly required.

Pathology-supported genetic testing as a method for disability prevention in multiple sclerosis (MS). Part II. Insights from two MS cases.

In Part I of this Review we evaluated the scientific evidence for a Metabolic Model of multiple sclerosis (MS). Part II outlines the implementation of an adaptive pathology-supported genetic testing (PSGT) algorithm aimed at preventing/reversing disability in two illustrative MS cases, starting with a questionnaire-based risk assessment, including family history and lifestyle factors. Measurement of iron, vitamin B12, vitamin D, cholesterol and homocysteine levels identified biochemical deficits in both cases. Case 1, after following the PSGT program for 15 years, had an expanded disability status scale (EDSS) of 2.0 (no neurological sequelae) together with preserved brain volume on magnetic resonance imaging (MRI). A novel form of iron deficiency was identified in Case 1, as biochemical testing at each hospital submission due to MS symptoms showed low serum iron, ferritin and transferrin saturation, while hematological status and erythrocyte sedimentation rate measurement of systemic inflammation remained normal. Case 2 was unable to walk unaided until her EDSS improved from 6.5 to 4.0 over 12 months after implementation of the PSGT program, with amelioration of her suboptimal biochemical markers and changes to her diet and lifestyle, allowing her to regain independence. Genotype-phenotype correlation using a pathway panel of functional single nucleotide variants (SNVs) to facilitate clinical interpretation of whole exome sequencing (WES), elucidated the underlying metabolic pathways related to the biochemical deficits. A cure for MS will remain an elusive goal if separated from nutritional support required for production and maintenance of myelin, which can only be achieved by a lifelong investment in wellness.

Iron homeostasis in host and gut bacteria - a complex interrelationship.

Iron deficiency is the most frequent nutritional deficiency in the world with an estimated 1.4 billion people affected. The usual way to fight iron deficiency is iron fortification, but this approach is not always effective and can have undesirable side effects including an increase in the growth and virulence of gut bacterial pathogens responsible for diarrhea and gut inflammation. Iron is mainly absorbed in the duodenum and is tightly regulated in mammals. Unabsorbed iron enters the colonic lumen where many microorganisms, referred to as gut microbiota, reside. Iron is essential for these bacteria, and its availability consequently affects this microbial ecosystem. The aim of this review is to provide further insights into the complex relationship between iron and gut microbiota. Given that overcoming anemia caused by iron deficiency is still a challenge today, gut microbiota could help identify more efficient ways to tackle this public health problem.

Effect of sevoflurane on iron homeostasis and toxicity in the brain of mice.

Sevoflurane (Sev), a commonly used volatile anesthetic, could induce nerve damage and cognitive deficiency. Oxidative stress induced by iron overload promotes nerve damage and cell apoptosis in the brain. This study revealed a new toxic mechanism of Sev to the brain occurred through the dysfunction of iron metabolism. Twelve-month-old C57BL/6 mice were randomly assigned to the following three groups: control group; 2% Sev (6 h) group; and Sev plus iron deficiency group. Iron levels and iron metabolism-related proteins and apoptosis-related factors in hippocampus and cortex tissues were detected by using synchrotron radiation micro-X-ray fluorescence (µ-XRF) and western blotting. Our results showed that a decline in cognitive function was observed in mice treated with Sev. Sev significantly induced iron accumulation through upregulating ferritin and downregulating transferrin receptor 1 which involved in ferroportin1 (Fpn1)/hepcidin pathway and increasing reactive oxygen species (ROS) and malondialdehyde (MDA) content of hippocampus and cortex. Sev aggravated BACE1 expression and Aß accumulation. Changes in the ratio of Bcl2/Bax and Tau/p-Tau intensified the cell apoptosis in hippocampus and cortex tissues. Interestingly, the cognitive deficiency and neurotoxicity induced by Sev could be ameliorated significantly by feeding a low-iron diet to mice prior to anesthesia. The data uncovered a new lesion mechanism of Sev from the role of iron metabolism. This study also suggested that the reduction in iron levels could protect the brain against neurological damage induced by Sev.

Prion Protein on Human Leukocytes Is Reduced in Iron Deficiency - Possible Implications for Age-related Macular Degeneration?

MATERIALS AND METHODS: Patients presenting to the department of ophthalmology of the Medical University of Graz for reasons unrelated to prion diseases were enrolled. Parameters of iron metabolism, including ferritin and soluble transferrin receptor were measured by routine laboratory tests. Serum prion protein was determined by enzyme-linked immunosorbent assay. Surface prion protein on CD14+ monocytes and CD4+ T cells was analyzed by fluorescence activated cell sorting. RESULTS: 95 patients were enrolled. Soluble transferrin receptor correlated significantly with prion protein levels on CD14+POM1+ monocytes (P = .001, r = -0.7) and on CD4+POM1+ T cells (P = .01, r = -0.62). CONCLUSION: Our findings suggest a connection between the physiological function of the prion protein and iron metabolism in humans.

H-Ferritin Produced by Myeloid Cells Is Released to the Circulation and Plays a Major Role in Liver Iron Distribution during Infection.

During infections, the host redistributes iron in order to starve pathogens from this nutrient. Several proteins are involved in iron absorption, transport, and storage. Ferritin is the most important iron storage protein. It is composed of variable proportions of two peptides, the L- and H-ferritins (FTL and FTH). We previously showed that macrophages increase their expression of FTH1 when they are infected in vitro with Mycobacterium avium, without a significant increase in FTL. In this work, we investigated the role of macrophage FTH1 in M. avium infection in vivo. We found that mice deficient in FTH1 in myeloid cells are more resistant to M. avium infection, presenting lower bacterial loads and lower levels of proinflammatory cytokines than wild-type littermates, due to the lower levels of available iron in the tissues. Importantly, we also found that FTH1 produced by myeloid cells in response to infection may be found in circulation and that it plays a key role in iron redistribution. Specifically, in the absence of FTH1 in myeloid cells, increased expression of ferroportin is observed in liver granulomas and increased iron accumulation occurs in hepatocytes. These results highlight the importance of FTH1 expression in myeloid cells for iron redistribution during infection.