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.