A crosstalk between hepcidin and IRE/IRP pathways controls ferroportin expression and determines serum iron levels in mice

  1. Edouard Charlebois
  2. Carine Fillebeen
  3. Angeliki Katsarou
  4. Aleksandr Rabinovich
  5. Kazimierz Wisniewski
  6. Vivek Venkataramani
  7. Bernhard Michalke
  8. Anastasia Velentza
  9. Kostas Pantopoulos  Is a corresponding author
  1. McGill University, Canada
  2. Ferring Research Institute Inc, United States
  3. University Hospital Frankfurt, Germany
  4. Helmholtz Zentrum München, Germany

Abstract

The iron hormone hepcidin is transcriptionally activated by iron or inflammation via distinct, partially overlapping pathways. We addressed how iron affects inflammatory hepcidin levels and the ensuing hypoferremic response. Dietary iron overload did not mitigate hepcidin induction in LPS-treated wt mice but prevented effective inflammatory hypoferremia. Likewise, LPS modestly decreased serum iron in hepcidin-deficient Hjv-/- mice, model of hemochromatosis. Synthetic hepcidin triggered hypoferremia in control but not iron-loaded wt animals. Furthermore, it dramatically decreased hepatic and splenic ferroportin in Hjv-/- mice on standard or iron-deficient diet, but only triggered hypoferremia in the latter. Mechanistically, iron antagonized hepcidin responsiveness by inactivating IRPs in the liver and spleen, to stimulate ferroportin mRNA translation. Prolonged LPS treatment eliminating ferroportin mRNA permitted hepcidin-mediated hypoferremia in iron-loaded mice. Thus, de novo ferroportin synthesis is critical determinant of serum iron and finetunes hepcidin-dependent functional outcomes. Our data uncover a crosstalk between hepcidin and IRE/IRP systems that controls tissue ferroportin expression and determines serum iron levels. Moreover, they suggest that hepcidin supplementation therapy is more efficient combined with iron depletion.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file

Article and author information

Author details

  1. Edouard Charlebois

    Department of Medicine, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  2. Carine Fillebeen

    Department of Medicine, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Angeliki Katsarou

    Department of Medicine, McGill University, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Aleksandr Rabinovich

    Ferring Research Institute Inc, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Kazimierz Wisniewski

    Ferring Research Institute Inc, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Vivek Venkataramani

    Department of Medicine II, University Hospital Frankfurt, Frankfurt, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Bernhard Michalke

    Research Unit Analytical BioGeoChemistry, Helmholtz Zentrum München, Neuherberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Anastasia Velentza

    Ferring Research Institute Inc, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Kostas Pantopoulos

    Department of Medicine, McGill University, Montreal, Canada
    For correspondence
    kostas.pantopoulos@mcgill.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2305-0057

Funding

Canadian Institutes of Health Research (PJT-159730)

  • Kostas Pantopoulos

Fonds de Recherche du Québec - Santé

  • Edouard Charlebois

Deutsche Forschungsgemeinschaft (SPP 2306)

  • Vivek Venkataramani
  • Bernhard Michalke

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experimental procedures were approved by the Animal Care Committee of McGill University (protocol 4966).

Reviewing Editor

  1. Yelena Ginzburg, Icahn School of Medicine at Mount Sinai, United States

Publication history

  1. Preprint posted: November 1, 2021 (view preprint)
  2. Received: June 23, 2022
  3. Accepted: August 30, 2022
  4. Accepted Manuscript published: September 6, 2022 (version 1)
  5. Version of Record published: September 22, 2022 (version 2)

Copyright

© 2022, Charlebois et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Edouard Charlebois
  2. Carine Fillebeen
  3. Angeliki Katsarou
  4. Aleksandr Rabinovich
  5. Kazimierz Wisniewski
  6. Vivek Venkataramani
  7. Bernhard Michalke
  8. Anastasia Velentza
  9. Kostas Pantopoulos
(2022)
A crosstalk between hepcidin and IRE/IRP pathways controls ferroportin expression and determines serum iron levels in mice
eLife 11:e81332.
https://doi.org/10.7554/eLife.81332
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