Journal article
Isocitrate ameliorates anemia by suppressing the erythroid iron restriction response
The Journal of clinical investigation, Vol.123(8), pp.3614-3623
08/01/2013
DOI: 10.1172/jci68487
PMCID: PMC3726169
PMID: 23863711
Abstract
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.
Details
- Title: Subtitle
- Isocitrate ameliorates anemia by suppressing the erythroid iron restriction response
- Creators
- Chanté L Richardson - University of VirginiaLorrie L DelehantyGrant C BullockClaudia M RivalKenneth S TungDonald L Kimpel - University of VirginiaSara Gardenghi - Cornell UniversityStefano Rivella - Cornell UniversityAdam N Goldfarb
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.123(8), pp.3614-3623
- DOI
- 10.1172/jci68487
- PMID
- 23863711
- PMCID
- PMC3726169
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Grant note
- P50 HD028934 / NICHD NIH HHS DK090926 / NIDDK NIH HHS PA-08-190/DK090926 / NIDDK NIH HHS P30 CA044579 / NCI NIH HHS R01 DK079924 / NIDDK NIH HHS T32 GM007055 / NIGMS NIH HHS K08-HL093355 / NHLBI NIH HHS R01 AI041236 / NIAID NIH HHS R01 DK090926 / NIDDK NIH HHS DK079924 / NIDDK NIH HHS K08 HL093355 / NHLBI NIH HHS T32 GM7055 / NIGMS NIH HHS
- Language
- English
- Date published
- 08/01/2013
- Academic Unit
- Pathology
- Record Identifier
- 9984697641402771
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