Isocitrate ameliorates anemia by suppressing the erythroid iron restriction response
Chanté L. Richardson, … , Stefano Rivella, Adam N. Goldfarb
Chanté L. Richardson, … , Stefano Rivella, Adam N. Goldfarb
Published July 25, 2013
Citation Information: J Clin Invest. 2013;123(8):3614-3623. https://doi.org/10.1172/JCI68487.
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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

Chanté L. Richardson, Lorrie L. Delehanty, Grant C. Bullock, Claudia M. Rival, Kenneth S. Tung, Donald L. Kimpel, Sara Gardenghi, Stefano Rivella, Adam N. Goldfarb

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Figure 2

Iron restriction and IC oppositely modulate the responsiveness of erythroid progenitors to the inflammatory cytokine IFN-γ.

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Iron restriction and IC oppositely modulate the responsiveness of erythr...
Human CD34+ primary progenitors were cultured 5 days in erythroid medium with TSATs of 100%, 15%, or 15% + IC. Where indicated, cultures also contained human IFN-γ. (A) The cooperative inhibition of erythroid differentiation by iron restriction and IFN-γ is reversed by IC treatment. Cells stained with fluorescent antibodies to the erythroid antigen GPA and to CD41 were analyzed by flow cytometry, with percentages of positive cells indicated. (B) Summary graphs of 4 independent experiments conducted as in A, showing mean ± SEM for IFN-γ response index for viability, proliferation, and differentiation. This index consists of the ratio of values obtained in cultures with IFN-γ divided by values obtained in cultures without IFN-γ. Thus, values greater than 1 represent a positive effect of IFN-γ, and values less than 1 represent an inhibitory effect. (C) Transient IC exposure suffices for complete rescue of differentiation. Human progenitors were cultured in erythroid medium with 15% TSAT and IFN-γ. Where indicated, IC was included in the medium for the first 24 hours of culture followed by wash out and continuation in IC-free erythroid medium with 15% TSAT and IFN-γ. Cells on day 5 underwent flow cytometry for GPA expression with gating on the viable fraction. n = 3. All data are mean ± SEM. *P < 0.05; ***P < 0.001.