Isocitrate ameliorates anemia by suppressing the erythroid iron restriction response

J Clin Invest. 2013 Aug;123(8):3614-23. doi: 10.1172/JCI68487. Epub 2013 Jul 25.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aconitate Hydratase / metabolism
  • Anemia / drug therapy*
  • Anemia / metabolism
  • Anemia / pathology
  • Animals
  • Cells, Cultured
  • Erythroid Cells / drug effects*
  • Erythroid Cells / enzymology
  • Erythropoiesis / drug effects*
  • Female
  • Humans
  • Interferon-gamma / physiology
  • Iron / deficiency*
  • Isocitrates / pharmacology*
  • Isocitrates / therapeutic use
  • Protein Kinase C / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Rats
  • Rats, Inbred Lew
  • Signal Transduction
  • Trans-Activators / metabolism
  • Transcriptional Activation

Substances

  • Isocitrates
  • Proto-Oncogene Proteins
  • Trans-Activators
  • proto-oncogene protein Spi-1
  • Interferon-gamma
  • isocitric acid
  • Iron
  • Protein Kinase C
  • Aconitate Hydratase