Role of Ceruloplasmin in Macrophage Iron Efflux during Hypoxia
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The reticuloendothelial system has a central role in erythropoiesis and iron homeostasis. An important function of reticuloendothelial macrophages is phagocytosis of senescent red blood cells. The iron liberated from heme is recycled for delivery to erythrocyte precursors for a new round of hemoglobin synthesis. The molecular mechanism by which recycled iron is released from macrophages remains unresolved. We have investigated the mechanism of macrophage iron efflux, focusing on the role of ceruloplasmin (Cp), a copper protein with a potent ferroxidase activity that converts Fe2+ to Fe3+ in the presence of molecular oxygen. As shown by others, Cp markedly increased iron binding to apotransferrin at acidic pH; however, the physiological significance of this finding is uncertain because little stimulation was observed at neutral pH. Introduction of a hypoxic atmosphere resulted in marked Cp-stimulated binding of iron to apotransferrin at physiological pH. The role of Cp in cellular iron release was examined in U937 monocytic cells induced to differentiate to the macrophage lineage. Cp added at its normal plasma concentration increased the rate of 55Fe release from U937 cells by about 250%. The stimulation was absolutely dependent on the presence of apotransferrin and hypoxia. Cp-stimulated iron release was confirmed in mouse peritoneal macrophages. Stimulation of iron release required an intracellular "labile iron pool" that was rapidly depleted in the presence of Cp and apotransferrin. Ferroxidase-mediated loading of iron into apotransferrin was critical for iron release because ferroxidase-deficient Cp was inactive and because holotransferrin could not substitute for apotransferrin. The extracellular iron concentration was critical as shown by inhibition of iron release by exogenous free iron, and marked enhancement of release by an iron chelator. Together these data show that Cp stimulates iron release from macrophages under hypoxic conditions by a ferroxidase-dependent mechanism, possibly involving generation of a negative iron gradient.
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HIF-HRE interaction in response to hypoxia stimulates iron release from macrophages by inducing Hmox1 and Fpn1 as well as ceruloplasmin.
“HIF-HRE interaction in response to hypoxia thus stimulates iron release from macrophages by inducing Hmox1 and Fpn1 as well as one of its associated ferroxidases, ceruloplasmin [37, 63, 200].”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [200]
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- Authors
- Sarkar, J., Seshadri, V., Tripoulas, N. A., Ketterer, M. E., & Fox, P. L.
- Affiliations
- Cleveland Clinic (US)
- Northern Arizona University (US)
- Corresponding author
- Fox, Paul L.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-11
- Volume
- 278
- Issue
- 45
- Pages
- 44018-44024
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2070771807
- Cited by
- 101
- References
- 61
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 2 · 2020: 3 · 2019: 1 · 2018: 2 · 2017: 4 · 2016: 4 · 2015: 7 · 2014: 7 · 2013: 7 · 2012: 5
- FWCI
- 2.65
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Science Foundation (0116804)
- National Institutes of Health (HL29582)
- National Heart, Lung, and Blood Institute (HL 29582, HL67725, P01HL029582, R01HL067725)
- Division of Chemistry
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Keywords
- ceruloplasmin, hypoxia, iron homeostasis, apotransferrin, ferroxidase activity, erythropoiesis, reticuloendothelial system, labile iron pool, U937 cells, peritoneal macrophages, iron chelation
- MeSH terms
- Animals, Apoproteins, Cell Differentiation, Cell Line, Ceruloplasmin, Ferric Compounds, Ferrous Compounds, Humans, Hydrogen-Ion Concentration, Iron, Iron Radioisotopes, Kinetics, Macrophages, Mice, Inbred C57BL, Monocytes, Oxidation-Reduction, Oxygen, Tetradecanoylphorbol Acetate, Transferrin, Cell Hypoxia, Macrophages, Peritoneal, Mice
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