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The function of heme-regulated eIF2 kinase in murine iron homeostasis and macrophage maturation
Sijin Liu1, Rajasekhar N.V.S. Suragani1, Fudi Wang2, Anping Han1, Wanting Zhao1, Nancy C. Andrews2 and Jane-Jane Chen1
1Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. 2Division of Hematology/Oncology, Children’s Hospital Boston and Harvard Medical School, Boston, Massachusetts, USA.
Address correspondence to: Jane-Jane Chen, E25-545, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA. Phone: (617) 253-9674; Fax: (617) 253-3459; E-mail: j-Received for publication March 9, 2007, and accepted in revised form July 18, 2007.
Heme-regulated eIF2 kinase (HRI) plays an essential protective role in anemias of iron deficiency, erythroid protoporphyria, and ß-thalassemia. In this study, we report that HRI protein is present in murine macrophages, albeit at a lower level than in erythroid precursors. Hri–/– mice exhibited impaired macrophage maturation and a weaker antiinflammatory response with reduced cytokine production upon LPS challenge. The level of production of hepcidin, an important player in the pathogenesis of the anemia of inflammation, was significantly decreased in Hri–/– mice, accompanied by decreased splenic macrophage iron content and increased serum iron content. Hepcidin expression was also significantly lower, with a concomitant increase in serum iron in Hri–/– mice upon LPS treatment. We also demonstrated an impairment of erythrophagocytosis by Hri–/– macrophages both in vitro and in vivo under chronic hemolytic anemia, providing evidence for the role of HRI in recycling iron from senescent red blood cells. This work demonstrates that HRI deficiency attenuates hepcidin expression and iron homeostasis in mice, indicating a potential role for HRI in the anemia of inflammation.
