Blunted hepcidin response to inflammation in the absence of Hfe and transferrin receptor 2.
The induction of the iron-regulatory peptide hepcidin by proinflammatory cytokines is thought to result in the withholding of iron from invading pathogens. Hfe and transferrin receptor 2 (Tfr2) are involved in the homeostatic regulation of hepcidin and their disruption causes hereditary hemochromatosis (HH). To determine whether either Hfe or Tfr2 is involved in the inflammatory pathway regulating hepcidin, we analyzed the effect of inflammation in 3 mouse models of HH. The inflammatory response and indicators of iron homeostasis were measured in wild-type, Hfe(-/-), Tfr2(-/-), and Hfe(-/-)/Tfr2(-/-) mice injected with lipopolysaccharide (LPS). The administration of LPS significantly reduced serum iron in wild-type and Hfe(-/-) mice, with smaller reductions in Tfr2(-/-) and Hfe(-/-)/Tfr2(-/-) mice. Low basal levels of hepcidin in the Hfe(-/-)/Tfr2(-/-) mice were increased in response to LPS, but remained significantly lower than in the other strains of mice. These results suggest that despite the absence of Hfe and Tfr2, hepcidin is responsive to inflammation; however, the low basal expression and subsequent low levels of circulating hepcidin are insufficient to reduce serum iron effectively. This suggests that in HH, the iron-withholding response to invading pathogens may be inadequate, and this is especially the case in the absence of both Hfe and Tfr2.
The Membrane Transport Laboratory, Queensland Institute of Medical Research, The University of Queensland, Brisbane, Australia.
Daniel F
DF
Wallace
Cameron J
CJ
McDonald
Lesa
L
Ostini
V Nathan
VN
Subramaniam
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000097:blood* / Q000276:immunology; D015153:Blotting, Western; D004195:Disease Models, Animal; D006432:Hemochromatosis / Q000276:immunology / Q000378:metabolism*; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D007501:Iron / Q000097:blood; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011990:Receptors, Transferrin / Q000172:deficiency* / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D023181:Antimicrobial Cationic Peptides; C579599:Hamp protein, mouse; D000071020:Hemochromatosis Protein; D064451:Hepcidins; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D011990:Receptors, Transferrin; C503641:TFR2 protein, mouse; D007501:Iron