Isocitrate ameliorates anemia by suppressing the erythroid iron restriction response

Richardson, Chanté; Delehanty, Lorrie L.; Bullock, Grant C.; Rival, Claudia; Tung, Kenneth S. K.; Kimpel, Donald L.; Gardenghi, Sara; Rivella, Stefano; Goldfarb, Adam N.

doi:10.1172/jci68487

Cited by 39 publications

(40 citation statements)

References 59 publications

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“…inflammation (Goodnough et al, 2010), where iron restriction sensitizes cells to the inhibitory effects of inflammatory cytokines (Richardson et al, 2013). However, we do not detect any IL6, the key inducer of hepcidin and mediator of inflammation (Hom et al, 2015;Wang and Babitt, 2016).…”

Section: Discussioncontrasting

confidence: 65%

Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development

Planutis

Xue

Trainor³

et al. 2017

Development

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Transcription factor control of cell-specific downstream targets can be significantly altered when the controlling factor is mutated. We show that the semi-dominant neonatal anemia (Nan) mutation in the EKLF/ KLF1 transcription factor leads to ectopic expression of proteins that are not normally expressed in the red blood cell, leading to systemic effects that exacerbate the intrinsic anemia in the adult and alter correct development in the early embryo. Even when expressed as a heterozygote, the Nan-EKLF protein accomplishes this by direct binding and aberrant activation of genes encoding secreted factors that exert a negative effect on erythropoiesis and iron use. Our data form the basis for a novel mechanism of physiological deficiency that is relevant to human dyserythropoietic anemia and likely other disease states.

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Section: Discussioncontrasting

confidence: 65%

Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development

Planutis

Xue

Trainor³

et al. 2017

Development

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“…Interestingly, we observed significantly increased leukocytosis in WT B abortus compared with Hamp-KO B abortus mice (supplemental Figure 3B). Following recent suggestions, 33,35 we suspect that the increase in IFN-g together with hepcidin-mediated iron restriction may promote erythropoietic suppression and a shift to leukocyte production. We speculate that delayed or inadequate shift to leukocyte production in Hamp-KO mice may have interfered with the neutralization of B abortus-associated pathogenic molecules, thereby increasing mortality.…”

mentioning

confidence: 54%

A mouse model of anemia of inflammation: complex pathogenesis with partial dependence on hepcidin

Kim

Fung²,

Parikh³

et al. 2014

Blood

126

116

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• An injection of heat-killedBrucella abortus in mice causes prolonged anemia with features similar to human anemia of inflammation.• Ablation of hepcidin ameliorates anemia of inflammation in this model and allows faster recovery.Anemia is a common complication of infections and inflammatory diseases, but the few mouse models of this condition are not well characterized. We analyzed in detail the pathogenesis of anemia induced by an injection of heat-killed Brucella abortus and examined the contribution of hepcidin by comparing wild-type (WT) to iron-depleted hepcidin-1 knockout (Hamp-KO) mice. B abortus-treated WT mice developed severe anemia with a hemoglobin nadir at 14 days and partial recovery by 28 days. After an early increase in inflammatory markers and hepcidin, WT mice manifested hypoferremia, despite iron accumulation in the liver. Erythropoiesis was suppressed between days 1 and 7, and erythrocyte destruction was increased as evidenced by schistocytes on blood smears and shortened red blood cell lifespan. Erythropoietic recovery began after 14 days but was iron restricted. In B abortus-treated Hamp-KO compared with WT mice, anemia was milder, not iron restricted, and had a faster recovery. Similarly to severe human anemia of inflammation, the B abortus model shows multifactorial pathogenesis of inflammatory anemia including iron restriction from increased hepcidin, transient suppression of erythropoiesis, and shortened erythrocyte lifespan. Ablation of hepcidin relieves iron restriction and improves the anemia. (Blood. 2014;123(8):1129-1136 Introduction Anemia of inflammation (AI) is a feature of a wide spectrum of inflammatory disorders, including connective tissue disease, infections, certain malignancies, and chronic kidney disease.1 AI is typically a normocytic normochromic anemia with a shortened erythrocyte lifespan and suppressed erythropoiesis, despite adequate levels of circulating erythropoietin.2 Perhaps the most consistent feature of AI is a derangement of systemic iron homeostasis characterized by hypoferremia with intact iron stores 1 and decreased availability of iron for erythrocyte production.Hepcidin, a 25-amino acid peptide hormone produced primarily by hepatocytes, 3 is the principal regulator of iron homeostasis in health and during inflammation. 4 Excessive production of this hormone causes iron sequestration in macrophages and hypoferremia, as was shown in transgenic mice with hepcidin overexpression 5 and in the human genetic syndrome of hepcidin excess, iron-refractory iron-deficiency anemia due to mutations in matriptase-2/TMPRSS6. 6 Hepcidin acts by binding to ferroportin, the sole known cellular iron exporter, displayed on the surface of macrophages, hepatocytes, and the basolateral membranes of enterocytes. Hepcidin binding to ferroportin causes ferroportin endocytosis and degradation.7 During inflammation or infection, hepcidin is strongly induced, largely by interleukin 6 (IL-6) 8 via the Janus kinase-signal transducer and activator of transcription pathway.9-11 The ex...

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“…In a rodent model for the anemia of chronic disease, administration of isocitrate bypassed aconitase deficiency to relieve some erythropoietic defects. 50 These interesting findings may illustrate new approaches for treating various forms of anemia, although further work is required.…”

Section: Stimulating Erythropoiesismentioning

confidence: 98%

Anemia: progress in molecular mechanisms and therapies

Sankaran

Weiss

2015

Nat Med

231

198

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Anemia is a major source of morbidity and mortality worldwide. Here we review recent insights into how red blood cells (RBCs) are produced, the pathogenic mechanisms underlying various forms of anemia, and novel therapies derived from these findings. It is likely that these new insights, mainly arising from basic scientific studies, will contribute immensely to understanding frequently debilitating forms of anemia and the ability to treat affected patients. Major worldwide diseases that may stand to benefit from the new advances include the hemoglobinopathies (β-thalassemia and sickle cell disease), rare genetic disorders of red blood cell production, and anemias associated with chronic kidney disease, inflammation, and cancer. Promising new treatment approaches include drugs that target recently defined pathways in red blood cell production, iron metabolism, and fetal globin gene expression, as well as gene therapies using improved viral vectors and newly developed genome editing technologies.

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Isocitrate ameliorates anemia by suppressing the erythroid iron restriction response

Cited by 39 publications

References 59 publications

Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development

Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development

A mouse model of anemia of inflammation: complex pathogenesis with partial dependence on hepcidin

Anemia: progress in molecular mechanisms and therapies

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