Isocitrate ameliorates anemia by suppressing the erythroid iron restriction response

The unique sensitivity of early red cell progenitors to iron deprivation, known as the erythroid iron restriction response, serves as a basis for human anemias globally. This response impairs erythropoietin-driven erythropoiesis and underlies erythropoietic repression in iron deficiency anemia. Mech...

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Bibliographic Details
Published in:The Journal of clinical investigation 2013-08, Vol.123 (8), p.3614-3623
Main Authors: Richardson, Chanté L, Delehanty, Lorrie L, Bullock, Grant C, Rival, Claudia M, Tung, Kenneth S, Kimpel, Donald L, Gardenghi, Sara, Rivella, Stefano, Goldfarb, Adam N
Format: Article
Language:English
Subjects:
Aconitate Hydratase - metabolism
Anemia
Anemia - drug therapy
Anemia - metabolism
Anemia - pathology
Animals
Arthritis
Biomedical research
Cells, Cultured
Colleges & universities
Cytokines
Erythroid Cells - drug effects
Erythroid Cells - enzymology
Erythropoiesis - drug effects
Erythropoietin
Female
Flow cytometry
Humans
Interferon-gamma - physiology
Iron - deficiency
Isocitrates - pharmacology
Isocitrates - therapeutic use
Mortality
Protein Kinase C - metabolism
Proto-Oncogene Proteins - metabolism
Rats
Rats, Inbred Lew
Signal Transduction
Software
Technological change
Trans-Activators - metabolism
Transcriptional Activation
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Summary:The unique sensitivity of early red cell progenitors to iron deprivation, known as the erythroid iron restriction response, serves as a basis for human anemias globally. This response impairs erythropoietin-driven erythropoiesis and underlies erythropoietic repression in iron deficiency anemia. Mechanistically, the erythroid iron restriction response results from inactivation of aconitase enzymes and can be suppressed by providing the aconitase product isocitrate. Recent studies have implicated the erythroid iron restriction response in anemia of chronic disease and inflammation (ACDI), offering new therapeutic avenues for a major clinical problem; however, inflammatory signals may also directly repress erythropoiesis in ACDI. Here, we show that suppression of the erythroid iron restriction response by isocitrate administration corrected anemia and erythropoietic defects in rats with ACDI. In vitro studies demonstrated that erythroid repression by inflammatory signaling is potently modulated by the erythroid iron restriction response in a kinase-dependent pathway involving induction of the erythroid-inhibitory transcription factor PU.1. These results reveal the integration of iron and inflammatory inputs in a therapeutically tractable erythropoietic regulatory circuit.
ISSN:0021-9738
1558-8238
DOI:10.1172/jci68487