title: Isocitrate ameliorates anemia by suppressing the erythroid iron restriction response.
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.
authors.affiliation: Department of Pathology, University of Virginia, School of Medicine, Charlottesville, Virginia, USA.
authors.forename: Chanté L
authors.initials: CL
authors.lastname: Richardson
authors.forename: Lorrie L
authors.initials: LL
authors.lastname: Delehanty
authors.forename: Grant C
authors.initials: GC
authors.lastname: Bullock
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Rival
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Tung
authors.forename: Donald L
authors.initials: DL
authors.lastname: Kimpel
authors.forename: Sara
authors.initials: S
authors.lastname: Gardenghi
authors.forename: Stefano
authors.initials: S
authors.lastname: Rivella
authors.forename: Adam N
authors.initials: AN
authors.lastname: Goldfarb
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000740:Anemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D041905:Erythroid Cells / Q000187:drug effects* / Q000201:enzymology; D004920:Erythropoiesis / Q000187:drug effects*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology; D000090463:Iron Deficiencies; D007523:Isocitrates / Q000494:pharmacology* / Q000627:therapeutic use; D011493:Protein Kinase C / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D000154:Aconitate Hydratase; D007371:Interferon-gamma; D007523:Isocitrates; D011493:Protein Kinase C; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C034219:isocitric acid