Comments for:
Abstract
Iron homeostasis plays a critical role in many physiological processes, notably synthesis of heme proteins. Dietary iron sensing and inflammation converge in the control of iron absorption and retention by regulating the expression of hepcidin, a regulator of the iron exporter ferroportin. Human mutations in the glycosylphosphatidylinositol-anchored protein hemojuvelin (HJV; also known as RGMc and HFE2) cause juvenile hemochromatosis, a severe iron overload disease, but the way in which HJV intersects with the iron regulatory network has been unclear. Here we show that, within the liver, mouse Hjv is selectively expressed by periportal hepatocytes and also that Hjv-mutant mice exhibit iron overload as well as a dramatic decrease in hepcidin expression. Our findings define a key role for Hjv in dietary iron sensing and also reveal that cytokine-induced inflammation regulates hepcidin expression through an Hjv-independent pathway.
Authors
Vera Niederkofler, Rishard Salie, Silvia Arber
Hemojuvelin deficiency blunts the normal hepcidin response to inflammation.
Submitter: Y Paul Goldberg | mrh@cmmt.ubc.ca
Xenon Pharmaceuticals, Inc., Burnaby, BC, Canada
Published August 26, 2005
Send correspondence to: Michael R. Hayden, MB ChB PhD FRCP(C) FRSC
University Killam Professor
Canada Research Chair, Human Genetics
Director & Sr Scientist, Centre for Molecular Medicine & Therapeutics, Child & Family Research Institute (CFRI), University of British Columbia
Professor of Medical Genetics, University of British Columbia
Centre for Molecular Medicine & Therapeutics 950 West 28th Avenue University of British Columbia Vancouver, B.C. V5Z 4H4 Tel.: (604) 875-3535 Fax: (604) 875-3819
August 17, 2005
Dear Dr. Andrew Marks, (Editor in Chief, Journal of Clinical Investigation)
We read with great interest the article by Niederkofler et al entitled "Hemojuvelin is essential for dietary iron sensing, and its mutation leads to iron overload".1
The authors performed a mouse knockout experiment targeting the recently identified Juvenile Hemochromatosis gene, hemojuvelin2, and characterized the iron overload phenotype of the hemojuvelin-mutant mice. They elegantly showed that hemojuvelin mutant mice display severe iron overload in the liver, pancreas, as well in the heart and kidney. Importantly, the hemojuvelin knockout mice were found to have a complete deficiency of hepcidin mRNA expression in the unstimulated state. This finding corroborates our clinical studies showing that patients with Juvenile Hemochromatosis and hemojuvelin mutations have a markedly suppressed urinary hepcidin excretion2.
It is now well established that acute and chronic inflammatory stimuli are able to induce hepcidin and that elevated hepcidin levels comprise a key component of the pathophysiological disturbances seen in the anemia of inflammation (AI)3,4. The excessive hepcidin in this condition prevents iron uptake in the gut and iron release from macrophages, which leads to the classical iron maldistribution seen in AI. Several inflammatory mediators have been shown to induce hepcidin including lipopolysaccharide (LPS) and IL-65,6.
We differ with the authors on their interpretation of the effect of acute inflammatory stimuli on hepcidin induction in the hemojuvelin-mutant mice. In Figure 4, they examined liver hepcidin mRNA production in the wildtype and mutant mice in response to a variety of inflammatory stimuli (LPS, IL-6 or TNFĄ). While it is clear that inflammatory stimuli induce hepcidin in both wildtype and mutant mice, in mutant mice the stimulated hepcidin expression remains markedly attenuated compared to wildtype animals. In fact, with each of the inflammatory stimuli used, the hepcidin mRNA level in mutant mice fails to achieve that of mock-treated wildtype animals. Although the chronic consequences of these changes in hepcidin expression need to be experimentally tested, the inflamed mutant mice would not be expected to develop anemia of inflammation because their hepcidin levels would be at most in the normal range.
Thus we differ with the conclusion that "hemojuvelin is dispensable for the induction of hepcidin through the inflammatory pathway". Our alternative formulation is that while there are two distinct pathways for the induction of hepcidin, the dietary iron sensing pathway and inflammatory pathway, the baseline level of hepcidin expression is dependent on hemojuvelin. The subsequent induction of hepcidin by inflammatory stimuli is superimposed on the baseline expression making the ultimate hepcidin expression dependent on both pathways. In a parallel publication, we showed that cell-associated hemojuvelin positively regulates hepcidin mRNA expression independent of the IL-6 pathway7. However, using a soluble hemojuvelin antagonist we were able to markedly attenuate hepcidin production in vitro despite the presence of IL-6. Similarly in this paper, hemojuvelin mutant animals treated with IL-6 show markedly lower hepcidin expression compared to their wildtype counterparts (approximately four-fold less). Thus, the absence of hemojuvelin importantly affects hepcidin mRNA expression, even during inflammation.
Taken together, these data support the idea that a hemojuvelin antagonist may be effective in attenuating the hepcidin response seen in the anemia of inflammation and may correct the iron disturbances seen in this condition.
Y Paul Goldberg* MB ChB PhD FRCPC
Rajender Kamboj* PhD
Michael R Hayden* MB ChB PhD FRCP(C) FRSC
Tomas Ganz** MD, PhD
Xenon Pharmaceuticals, Inc., Burnaby, BC, Canada*, and David Geffen School of Medicine at UCLA, Departments of Medicine and Pathology, Los Angeles, CA, USA**
Reference List
1. Niederkofler, V., Salie, R., & Arber, S. Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload. J Clin Invest 115, 2180-2186 (2005).
2. Papanikolaou, G. et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat.Genet. 36, 77-82 (2004).
3. Ganz, T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 102, 783-788 (2003).
4. Roy, C. N. & Andrews, N. C. Anemia of inflammation: the hepcidin link. Curr. Opin Hematol. 12, 107-111 (2005).
5. Nemeth, E. et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 113, 1271-1276 (2004).
6. Lee, P., Peng, H., Gelbart, T., Wang, L., & Beutler, E. Regulation of hepcidin transcription by interleukin-1 and interleukin-6. Proc.Natl.Acad Sci U.S.A 102, 1906-1910 (2005).
7. Lin, L., Goldberg, Y. P., & Ganz, T. Competitive regulation of hepcidin mRNA by soluble and cell-associated hemojuvelin. Blood (2005).
Corresponding Author:
Michael R. Hayden, MB ChB PhD FRCP(C) FRSC University Killam Professor Canada Research Chair, Human Genetics Director & Sr Scientist, Centre for Molecular Medicine & Therapeutics, Child & Family Research Institute (CFRI), University of British Columbia Professor of Medical Genetics, University of British Columbia
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