Mechanistic and Therapeutic Studies Related to Anemia of Chronic Disease and Inflammation

Richardson, Chante, Experimental Pathology - Graduate School of Arts and Sciences, University of Virginia
Goldfarb, Adam, Department of Pathology, University of Virginia
Moskaluk, Christopher, Department of Pathology, University of Virginia
Cross, Janet, Department of Pathology, Research, University of Virginia
Taylor, Ronald, Department of Biochemistry and Molecular Genetics, University of Virginia
Tung, Kenneth, Department of Pathology, University of Virginia
Douvas, Michael, Department of Medicine, Hematology and Oncology, University of Virginia

The erythroid iron restriction response (EIRR) results from lineage-selective inactivation of aconitase enzymes, causing diminished erythropoietin (Epo) responsiveness in early erythroid progenitors. Provision of exogenous isocitrate in either cell culture or murine models of iron deficiency restores Epo responsiveness and abrogates the erythropoietic block characteristic of the iron deprivation response. Although isocitrate administration can restore erythropoiesis in iron deficient mice, the response is transient. However, if inappropriate activation of the EIRR also contributes to anemias not actually caused by decreased body iron stores, isocitrate may provide a therapeutic benefit in those clinical settings. A major area of clinical controversy is the degree to which erythroid iron restriction contributes to anemia of chronic disease and inflammation (ACDI).

Numerous patients with chronic diseases such as kidney failure, cancer, and autoimmunity develop clinically significant anemias, collectively designated anemia of chronic disease and inflammation. ACDI arises from the diminished production of red cells by the bone marrow. In many patients, treatment with erythropoietin injections lessens the anemia and improves symptoms. However, erythropoietin treatment is expensive, places patients at risk for adverse side effects, and in many cases eventually loses its effectiveness. Two major abnormalities in ACDI underlie the defective marrow function and poor responsiveness to erythropoietin treatment. Firstly, defects in iron transport cause retention in storage pools and diminished delivery to the marrow red cell precursors, a situation known as iron restriction. Secondly, cells in the immune system secrete inflammatory mediators, most notably interferon γ (IFNγ) and tumor necrosis factor α (TNFα), which directly bind to marrow red cell precursors and inhibit their development into red cells.

This study shows that iron restriction causes the red cell precursors to become extremely sensitive to the inhibitory effects of inflammatory mediators. Providing the compound isocitrate blocks all inhibition by inflammatory mediators in cell culture experiments and eliminates anemia in a rat arthritis model of ACDI. Additionally, this study dissects the ability of iron restriction to alter the response of the red cell precursors to the key inflammatory mediator IFNγ. In particular, iron restriction specifically changes the patterns of signaling within the cell as it responds to the mediator in the environment. We define a pathway in which iron restriction and IFN act in a cooperative manner on early erythroid progenitors to increase PU.1 expression and interfere with its normal downregulation. Iron restriction and isocitrate exert their influences, at least in part, through alteration of PKC activation. Thus, we propose a model of ACDI in which iron restriction and inflammatory signaling are both required to attain a critical threshold of erythroid PU.1, which may then interfere with early stages of lineage commitment. Through its reversal of PKC activation by iron restriction, isocitrate may act to keep PU.1 levels below this critical threshold. The ability of isocitrate to reverse these signaling abnormalities provides new evidence for how it exerts its beneficial effects in ACDI.

PHD (Doctor of Philosophy)
anemia, inflammation, iron, PU.1, isocitrate, interferon gamma, anemia of chronic disease, erythropoiesis
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