Iron modulation of erythropoiesis is associated with Scribble-mediated control of the erythropoietin receptor

Khalil, Shadi; Delehanty, Lorrie L.; Grado, Stephen; Holy, Maja; White, Zollie; Freeman, Katie; Kurita, Ryo; Nakamura, Yukio; Bullock, Grant C.; Goldfarb, Adam N.

doi:10.1084/jem.20170396

Cited by 63 publications

(62 citation statements)

References 54 publications

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“…33 In iron deficiency, unbound TfR2 is targeted to lysosome degradation, resulting in a reduction of cell surface distribution of EpoR and an inhibition of erythroid differentiation. 34 Consistent with these earlier reports, our data show that iron deficiency downregulates TfR2 and EpoR that may contribute to inhibition of terminal erythroid differentiation.…”

Section: Effects Of Testosterone On the Expression Levels Of Erythrsupporting

confidence: 93%

The role of iron in mediating testosterone's effects on erythropoiesis in mice

et al. 2020

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Testosterone stimulates iron‐dependent erythropoiesis and suppresses hepcidin. To clarify the role of iron in mediating testosterone's effects on erythropoiesis, we induced iron deficiency in mice by feeding low iron diet. Iron‐replete and iron‐deficient mice were treated weekly with testosterone propionate or vehicle for 3 weeks. Testosterone treatment increased red cell count in iron‐replete mice, but, surprisingly, testosterone reduced red cell count in iron‐deficient mice. Splenic stress erythropoiesis was stimulated in iron‐deficient mice relative to iron‐replete mice, and further increased by testosterone treatment, as indicated by the increase in red pulp area, the number of nucleated erythroblasts, and expression levels of TfR1, GATA1, and other erythroid genes. Testosterone treatment of iron‐deficient mice increased the ratio of early‐to‐late erythroblasts in the spleen and bone marrow, and serum LDH level, consistent with ineffective erythropoiesis. In iron‐deficient mice, erythropoietin levels were higher but erythropoietin‐regulated genes were generally downregulated relative to iron‐replete mice, suggesting erythropoietin resistance. Conclusion: Testosterone treatment stimulates splenic stress erythropoiesis in iron‐replete as well as iron‐deficient mice. However, testosterone worsens anemia in iron‐deficient mice because of ineffective erythropoiesis possibly due to erythropoietin resistance associated with iron deficiency. Iron plays an important role in mediating testosterone's effects on erythropoiesis.

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Section: Effects Of Testosterone On the Expression Levels Of Erythrsupporting

confidence: 93%

The role of iron in mediating testosterone's effects on erythropoiesis in mice

et al. 2020

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“…Transferrin receptor 2 (TfR2) contributes to hepcidin induction in response to circulating iron in hepatocytes but is also expressed on erythroblasts. Erythroblast TfR2 interacts with the erythropoietin receptor (EpoR) to modulate sensitivity to Epo signalling via interactions with Scribble, a key regulator of cellular trafficking and signalling [116,117,118,119]. Together, this provides a plausible mechanism by which erythropoietic output can be adjusted during iron deficiency (reviewed in [120]).…”

Section: The Importance Of Iron Status For Different Physiologicalmentioning

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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“…What we do know is that the “iron restriction response” employs multiple iron-sensitive molecular pathways to inhibit the differentiation and proliferation of erythroblasts and cause anemia in iron-deficient states [ 31 – 34 ]. The proposed mechanisms involve mitochondrial aconitase enzymes [ 31 ], transferrin receptor 2 (TfR2) [ 32 , 33 ], and scribble-mediated EpoR regulation [ 34 ], as well as effects on the erythroblast cell cycle [ 35 ]. It is possible that the disease process causes erythroblasts in PV to be less sensitive to iron deficiency, allowing them to differentiate and proliferate despite iron restriction.…”

Section: Current Treatment Approaches For Polycythemia Vera Patientsmentioning

confidence: 99%

“… Persistent systemic iron deficiency may be a consequence of an aberrant iron restriction response in PV patients. Iron restriction is thought to involve the development of erythroblast resistance to Epo, decrease erythroid precursor sensitivity to inflammation in an Epo-independent manner, and selectively enable cell survival without inducing differentiation [ 31 – 34 ]. Thus, if iron restriction normally serves as a brake on erythropoiesis when iron availability is limited, aberrant inflammation-insensitive erythropoiesis in PV may hijack iron for hemoglobin synthesis at the expense of iron requirements for all other cell functions, depleting iron stores.…”

Section: Iron Metabolism In Polycythemia Veramentioning

confidence: 99%

Dysregulated iron metabolism in polycythemia vera: etiology and consequences

et al. 2018

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Polycythemia vera (PV) is a chronic myeloproliferative neoplasm. Virtually all PV patients are iron deficient at presentation and/or during the course of their disease. The co-existence of iron deficiency and polycythemia presents a physiological disconnect. Hepcidin, the master regulator of iron metabolism, is regulated by circulating iron levels, erythroblast secretion of erythroferrone, and inflammation. Both decreased circulating iron and increased erythroferrone levels, which occur as a consequence of erythroid hyperplasia in PV, are anticipated to suppress hepcidin and enable recovery from iron deficiency. Inflammation which accompanies PV is likely to counteract hepcidin suppression, but the relatively low serum ferritin levels observed suggest that inflammation is not a major contributor to the dysregulated iron metabolism. Furthermore, potential defects in iron absorption, aberrant hypoxia sensing and signaling, and frequency of bleeding to account for iron deficiency in PV patients have not been fully elucidated. Insufficiently suppressed hepcidin given the degree of iron deficiency in PV patients strongly suggests that disordered iron metabolism is an important component of the pathobiology of PV. Normalization of hematocrit levels using therapeutic phlebotomy is the most common approach for reducing the incidence of thrombotic complications, a therapy which exacerbates iron deficiency, contributing to a variety of non-hematological symptoms. The use of cytoreductive therapy in high-risk PV patients frequently works more effectively to reverse PV-associated symptoms in iron-deficient relative to iron-replete patients. Lastly, differences in iron-related parameters between PV patients and mice with JAK2 V617F and JAK2 exon 12 mutations suggest that specific regions in JAK2 may influence iron metabolism by nuanced changes of erythropoietin receptor signaling. In this review, we comprehensively discuss the clinical consequences of iron deficiency in PV, provide a framework for understanding the potential dysregulation of iron metabolism, and present a rationale for additional therapeutic options for iron-deficient PV patients.

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Iron modulation of erythropoiesis is associated with Scribble-mediated control of the erythropoietin receptor

Cited by 63 publications

References 54 publications

The role of iron in mediating testosterone's effects on erythropoiesis in mice

The role of iron in mediating testosterone's effects on erythropoiesis in mice

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

Dysregulated iron metabolism in polycythemia vera: etiology and consequences

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