title: Normal systemic iron homeostasis in mice with macrophage-specific deletion of transferrin receptor 2.
abstract: Iron is an essential element, since it is a component of many macromolecules involved in diverse physiological and cellular functions, including oxygen transport, cellular growth, and metabolism. Systemic iron homeostasis is predominantly regulated by the liver through the iron regulatory hormone hepcidin. Hepcidin expression is itself regulated by a number of proteins, including transferrin receptor 2 (TFR2). TFR2 has been shown to be expressed in the liver, bone marrow, macrophages, and peripheral blood mononuclear cells. Studies from our laboratory have shown that mice with a hepatocyte-specific deletion of Tfr2 recapitulate the hemochromatosis phenotype of the global Tfr2 knockout mice, suggesting that the hepatic expression of TFR2 is important in systemic iron homeostasis. It is unclear how TFR2 in macrophages contributes to the regulation of iron metabolism. We examined the role of TFR2 in macrophages by analysis of transgenic mice lacking Tfr2 in macrophages by crossing Tfr2(f/f) mice with LysM-Cre mice. Mice were fed an iron-rich diet or injected with lipopolysaccharide to examine the role of macrophage Tfr2 in iron- or inflammation-mediated regulation of hepcidin. Body iron homeostasis was unaffected in the knockout mice, suggesting that macrophage TFR2 is not required for the regulation of systemic iron metabolism. However, peritoneal macrophages of knockout mice had significantly lower levels of ferroportin mRNA and protein, suggesting that TFR2 may be involved in regulating ferroportin levels in macrophages. These studies further elucidate the role of TFR2 in the regulation of iron homeostasis and its role in regulation of ferroportin and thus macrophage iron homeostasis.
authors.affiliation: Membrane Transport Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; and School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Gautam
authors.initials: G
authors.lastname: Rishi
authors.affiliation: Membrane Transport Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; and.
authors.forename: Eriza S
authors.initials: ES
authors.lastname: Secondes
authors.affiliation: Membrane Transport Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; and School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Wallace
authors.affiliation: Membrane Transport Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; and School of Medicine, The University of Queensland, Brisbane, Queensland, Australia Nathan.Subramaniam@qimrberghofer.edu.au.
authors.forename: V Nathan
authors.initials: VN
authors.lastname: Subramaniam
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000378:metabolism; D064451:Hepcidins / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D007501:Iron / Q000097:blood / Q000378:metabolism*; D019266:Iron, Dietary / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011990:Receptors, Transferrin / Q000235:genetics*; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; C579599:Hamp protein, mouse; D064451:Hepcidins; D019266:Iron, Dietary; D008070:Lipopolysaccharides; D011990:Receptors, Transferrin; C503641:TFR2 protein, mouse; D000098742:Ferroportin; D007501:Iron
keywords: hepcidin; iron metabolism; macrophages