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Kupffer cells modulate iron homeostasis in mice via regulation of hepcidin expression

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Abstract

Hepcidin, a small cationic liver derived peptide, is a master regulator of body iron homeostasis. Cytokines and iron availability have so far been identified as regulators of hepcidin expression. Herein, we investigated the functional role of Kupffer cells for hepcidin expression because of their vicinity to the hepatocytes and their importance for iron recycling via erythrophagocytosis. We investigated C57Bl6 mice and littermates, in which Kupffer cells were eliminated in vivo upon intravenous injection of liposome-encapsulated clodronate. Primary cultures of hepatocytes and Kupffer cells were used to study direct regulatory effects ex vivo. The in vivo depletion of Kupffer cells resulted in a significant increase in liver hepcidin expression, which was paralleled by a significant reduction in serum iron levels. The same pattern of regulation by Kupffer cell depletion was observed upon injection of bacterial lipopolysaccharide into mice and in primary (Hfe −/−) and in secondary iron-overloaded mice. Accordingly, the messenger ribonucleic acid (mRNA) concentrations of the hepcidin iron-sensing molecule hemojuvelin were not significantly changed upon Kupffer cell depletion. When primary hepatocytes were cocultivated with Kupffer cells or stimulated with a Kupffer cell-conditioned medium ex vivo, a significant reduction in hepatocyte hepcidin mRNA expression was observed. Our data suggest that Kupffer cells control body iron homeostasis by exerting negative regulatory signals toward hepcidin expression, which may be primarily referred to the secretion of yet unidentified hepcidin-suppressing molecules by Kupffer cells.

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Acknowledgments

Financial support by the Austrian Science Fund FWF-19664 and the Tiroler Wissenschaftsfonds are gratefully acknowledged.

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Authors and Affiliations

  1. Department of General Internal Medicine, Clinical Immunology and Infectious Diseases, Medical University of Innsbruck, Anichstr.35, 6020, Innsbruck, Austria

    Milan Theurl, Igor Theurl & Guenter Weiss

  2. Clinical Division of Nephrology, Medical University of Innsbruck, Innsbruck, Austria

    Kathrin Hochegger

  3. Institute of Pathology, Wagner-Jauregg Hospital, Linz, Austria

    Peter Obrist

  4. Membrane Transport Laboratory, The Queensland Institute of Medical Research, Brisbane, Australia

    Nathan Subramaniam

  5. Department of Molecular Cell Biology, Vrije Universiteit, Amsterdam, The Netherlands

    Nico van Rooijen

  6. Institute for the Physiology of Nutrition, Freising-Weihenstephan, Germany

    Klaus Schuemann

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  1. Milan Theurl
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Correspondence to Guenter Weiss.

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Theurl, M., Theurl, I., Hochegger, K. et al. Kupffer cells modulate iron homeostasis in mice via regulation of hepcidin expression. J Mol Med 86, 825–835 (2008). https://doi.org/10.1007/s00109-008-0346-y

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  • DOI: https://doi.org/10.1007/s00109-008-0346-y

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