Transient decrease of serum iron after acute erythropoietin treatment contributes to hepcidin inhibition by ERFE in mice

Artuso, Irene; Pettinato, Mariateresa; Nai, Antonella; Pagani, Alessia; Sardo, Ugo; Billoré, Benjamin; Lidonnici, Maria Rosa; Bennett, Cavan; Mandelli, Giacomo; Pasricha, Sant‐Rayn; Ferrari, G.; Camaschella, Clara; Kautz, Léon; Silvestri, Laura

doi:10.3324/haematol.2018.199810

Cited by 21 publications

(18 citation statements)

References 10 publications

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“…Recently, mouse studies have shown that acute rhEpo treatment downregulates hepcidin in an ERFE-independent manner by decreasing serum iron and Tfsat. 16 , 17 Moreover, the demonstration that rhEpo administration also downregulates hepcidin in mice lacking ERFE 18 suggests that prolonged erythropoietic stimulation inhibits hepcidin expression in mice by depleting iron stores, whereas ERFE represents an acute regulator of stress erythropoiesis. 18 Conversely, the present results show that in healthy humans ERFE responds even to low Epo levels which are not associated with an expansion of Hbmass, a functional marker of erythropoietic response.…”

Section: Discussionmentioning

confidence: 99%

Induction of erythroferrone in healthy humans by micro-dose recombinant erythropoietin or high-altitude exposure

Robach¹,

Gammella

Recalcati

et al. 2020

haematol

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The erythropoietin (Epo)-erythroferrone (ERFE)-hepcidin axis coordinates erythropoiesis and iron homeostasis. While mouse studies have established that Epo-induced ERFE production represses hepcidin synthesis by inhibiting hepatic BMP/SMAD signaling, evidence for the role of ERFE in humans is limited. To investigate the role of ERFE as a physiological erythroid regulator in humans, we conducted two studies: first, 24 males received six injections of saline (placebo), recombinant Epo (rhEpo) 20 UI kg-1 (micro-dose) or 50 UI kg-1 (low-dose). Second, we quantified ERFE in 22 subjects exposed to high altitude (3800 m) for 15 hours. In the first study, total hemoglobin mass (Hbmass) increased after low- but not after micro-dose injections, when compared to placebo. Serum ERFE levels were enhanced by rhEpo, remaining higher than after placebo for 48 (micro-dose) or 72 hours (low-dose) post-injections. Conversely, hepcidin levels decreased when Epo and ERFE arose, before any changes in serum iron parameters occurred. In the second study, serum Epo and ERFE increased at high altitude. The present results demonstrate that in healthy humans ERFE responds to slightly increased Epo levels not associated with Hbmass expansion and down-regulates hepcidin in an apparently iron-independent way. Notably, ERFE flags micro-dose Epo, thus holding promise as novel anti-doping biomarker.

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Section: Discussionmentioning

confidence: 99%

Induction of erythroferrone in healthy humans by micro-dose recombinant erythropoietin or high-altitude exposure

Robach¹,

Gammella

Recalcati

et al. 2020

haematol

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“…Iron recycling is essential not only to compensate chronic anemia but also in response to the acute expansion of erythropoiesis as after bleeding or erythropoietin stimulation. To verify the role played by NCOA4 in response to acute increase of iron demand in vivo, we exploited a published protocol (22,23), treating wt and Ncoa4-ko mice with a single EPO injection (8 UI/g body weight) to induce erythropoietic expansion, increased erythroferrone release (24) and inhibition of hepcidin. In normal mice, iron uptake from the diet and release from the stores are enhanced to supply erythropoiesis, resulting in a transient increase in the levels of serum iron 15 hours after EPO administration ( Figure 5A and (22)).…”

Section: Ncoa4-ko Mice Fail To Raise Circulating Iron Levels Upon Acumentioning

confidence: 99%

NCOA4-mediated ferritinophagy in macrophages is crucial to sustain erythropoiesis in mice

et al. 2020

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The Nuclear Receptor Coactivator 4 (NCOA4) promotes ferritin degradation and Ncoa4-ko mice in C57BL/6 background show microcytosis and mild anemia, aggravated by iron deficiency. To understand tissue specific contribution of NCOA4-mediated ferritinophagy we explored the effect of Ncoa4 genetic ablation in the iron-rich strain Sv129/J. Increased body iron content protects mice from anemia and, in basal conditions, Sv129/J Ncoa4-ko mice show only microcytosis; nevertheless, when fed a low-iron diet they develop a more severe anemia compared to wild-type animals. Reciprocal bone marrow (BM) transplantation from wild-type donors into Ncoa4-ko and from Ncoa4-ko into wild-type mice revealed that microcytosis and susceptibility to iron deficiency anemia depend on BM-derived cells. Erythropoiesis reconstitution with RBC count and hemoglobin normalization occurred at the same rate in transplanted animals independently of the genotype. Importantly, NCOA4 loss did not affect terminal erythropoiesis in iron deficiency, both in total and specific BM Ncoa4-ko animals compared to controls. On the contrary, upon a low iron diet, spleen from wild-type animals with Ncoa4-ko BM displayed marked iron retention compared to (wild-type BM) controls, indicating defective macrophage iron release in the former. Thus, EPO administration failed to mobilize iron from stores in Ncoa4-ko animals. Furthermore, Ncoa4 inactivation in thalassemic mice did not worsen the hematological phenotype. Overall our data reveal a major role for NCOA4-mediated ferritinophagy in macrophages to favor iron release for erythropoiesis, especially in iron deficiency.

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“…Erythroferrone suppresses liver hepcidin production through binding and inhibiting BMP6 and the related BMP family members, BMP5 and BMP7 [74] (which themselves are upregulated by iron in the absence of BMP6 [75]). Iron consumption by enhanced erythropoiesis also reduces the hepcidin-stimulatory signal from serum iron [76,77]. Similarly, during hypoxia, hepcidin can be suppressed through the cAMP Response Element Binding protein (CREB/CREB-H) pathways in response to high concentrations of Platelet-Derived Growth Factor-BB (PDGF-BB) activity [78].…”

Section: Regulation Of Iron Status During Early Childhoodmentioning

confidence: 99%

The Importance of Iron Status for Young Children in Low- and Middle-Income Countries: A Narrative Review

Armitage

Moretti

2019

Pharmaceuticals

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Early childhood is characterised by high physiological iron demand to support processes including blood volume expansion, brain development and tissue growth. Iron is also required for other essential functions including the generation of effective immune responses. Adequate iron status is therefore a prerequisite for optimal child development, yet nutritional iron deficiency and inflammation-related iron restriction are widespread amongst young children in low- and middle-income countries (LMICs), meaning iron demands are frequently not met. Consequently, therapeutic iron interventions are commonly recommended. However, iron also influences infection pathogenesis: iron deficiency reduces the risk of malaria, while therapeutic iron may increase susceptibility to malaria, respiratory and gastrointestinal infections, besides reshaping the intestinal microbiome. This means caution should be employed in administering iron interventions to young children in LMIC settings with high infection burdens. In this narrative review, we first examine demand and supply of iron during early childhood, in relation to the molecular understanding of systemic iron control. We then evaluate the importance of iron for distinct aspects of physiology and development, particularly focusing on young LMIC children. We finally discuss the implications and potential for interventions aimed at improving iron status whilst minimising infection-related risks in such settings. Optimal iron intervention strategies will likely need to be individually or setting-specifically adapted according to iron deficiency, inflammation status and infection risk, while maximising iron bioavailability and considering the trade-offs between benefits and risks for different aspects of physiology. The effectiveness of alternative approaches not centred around nutritional iron interventions for children should also be thoroughly evaluated: these include direct targeting of common causes of infection/inflammation, and maternal iron administration during pregnancy.

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Transient decrease of serum iron after acute erythropoietin treatment contributes to hepcidin inhibition by ERFE in mice

Cited by 21 publications

References 10 publications

Induction of erythroferrone in healthy humans by micro-dose recombinant erythropoietin or high-altitude exposure

Induction of erythroferrone in healthy humans by micro-dose recombinant erythropoietin or high-altitude exposure

NCOA4-mediated ferritinophagy in macrophages is crucial to sustain erythropoiesis in mice

The Importance of Iron Status for Young Children in Low- and Middle-Income Countries: A Narrative Review

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