Abstract
Abstract 4234
Anemia of chronic disease (ACD) is a complication accompanying many inflammatory diseases. The pro-inflammatory cytokine IFNγ has been implicated in this form of anemia, but the underlying mechanism remains unclear. Using a novel model for ACD, we demonstrate that IFNγ reduces both the lifespan and formation of red blood cells. Molecular analysis revealed that IFNγ induces expression of the transcription factors IRF-1 and PU.1 in both murine and human erythroid precursors. We found that IRF-1 binds to the promoter of PU.1 and induces its expression, leading to inhibition of erythropoiesis. Notably, downregulation of either IRF-1 or PU.1 expression is sufficient to overcome IFNγ-induced inhibition of erythropoiesis. PU.1 is a key transcription factor in hematopoietic lineage determination and its expression is sufficient to block erythroid differentiation and enhance myeloid differentiation. We therefore postulate that expression of IFNγ during infection can briefly shift the balance of erythroid towards myeloid differentiation, which will benefit the anti-microbial response. However, continuation of this feedback mechanism will hamper erythroid development and subsequently lead to anemia.
In conclusion, we here provide evidence for both a cellular and molecular mechanism by which IFNγ modulates erythropoiesis and how this contributes to the development of ACD.
No relevant conflicts of interest to declare.
Author notes
Asterisk with author names denotes non-ASH members.
