Isocitrate ameliorates anemia by suppressing the erythroid iron restriction response
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
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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Research Article Hematology

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 3

Influences of IFN-γ on erythroid aconitase activity and of iron restriction and IC on IFN-γ–mediated signaling.

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Influences of IFN-γ on erythroid aconitase activity and of iron restrict...
(A) Mitochondrial (M) and cytosolic (C) aconitase activities in human progenitors subjected to IFN-γ treatment ± iron restriction and IC. Gel-based enzymography was performed on extracts of cells cultured 4 days in erythroid medium under the indicated conditions. (B) Time-course analysis of the influence of iron restriction on IFN-γ activation of STAT1. Whole-cell lysates from human progenitors cultured in erythroid medium with IFN-γ ± iron restriction underwent immunoblot (IB) analysis of STAT1 phosphorylation and expression (C–E) Influences of iron restriction and IC on IFN-γ signaling via JAK-STAT. Progenitors cultured 3 days in erythroid medium under the indicated conditions were analyzed as in B. (F) Influences of iron restriction and IC on IFN-γ signaling via the GATE pathway. Cells cultured as in C–E underwent qRT-PCR assessment of IRF9 mRNA levels, with normalization to GAPDH. Results shown as fold increase relative to levels in cells cultured without IFN-γ and with 100% TSAT. All data are mean ± SEM. n = 3.