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The liver and muscle secreted HFE2-protein maintains central nervous system blood vessel integrity

Author

Listed:
  • Xue Fan Wang

    (University Health Network, Krembil Discovery Tower
    University of Toronto)

  • Robin Vigouroux

    (University Health Network, Krembil Discovery Tower
    University of Toronto)

  • Michal Syonov

    (University Health Network, Krembil Discovery Tower
    University of Toronto)

  • Yuriy Baglaenko

    (University Health Network, Krembil Discovery Tower)

  • Angeliki M. Nikolakopoulou

    (Keck School of Medicine of the University of Southern California)

  • Dene Ringuette

    (University Health Network, Krembil Discovery Tower
    University of Toronto)

  • Horea Rus

    (University of Maryland, School of Medicine, Department of Neurology)

  • Peter V. DiStefano

    (University Health Network)

  • Suzie Dufour

    (University Health Network, Krembil Discovery Tower)

  • Alireza P. Shabanzadeh

    (University Health Network, Krembil Discovery Tower)

  • Seunggi Lee

    (University Health Network, Krembil Discovery Tower
    University of Toronto)

  • Bernhard K. Mueller

    (BioNTech resano GmbH)

  • Jason Charish

    (University Health Network, Krembil Discovery Tower
    University of Toronto)

  • Hidekiyo Harada

    (University Health Network, Krembil Discovery Tower)

  • Jason E. Fish

    (University Health Network)

  • Joan Wither

    (University Health Network, Krembil Discovery Tower)

  • Thomas Wälchli

    (University Health Network, Krembil Discovery Tower
    University and University Hospital Zurich
    University Hospital Zurich
    University Health Network)

  • Jean-François Cloutier

    (The Neuro - Montreal Neurological Institute and Hospital)

  • Berislav V. Zlokovic

    (Keck School of Medicine of the University of Southern California)

  • Peter L. Carlen

    (University Health Network, Krembil Discovery Tower
    University of Toronto
    Keck School of Medicine of the University of Southern California)

  • Philippe P. Monnier

    (University Health Network, Krembil Discovery Tower
    University of Toronto
    University of Toronto)

Abstract

Liver failure causes breakdown of the Blood CNS Barrier (BCB) leading to damages of the Central-Nervous-System (CNS), however the mechanisms whereby the liver influences BCB-integrity remain elusive. One possibility is that the liver secretes an as-yet to be identified molecule(s) that circulate in the serum to directly promote BCB-integrity. To study BCB-integrity, we developed light-sheet imaging for three-dimensional analysis. We show that liver- or muscle-specific knockout of Hfe2/Rgmc induces BCB-breakdown, leading to accumulation of toxic-blood-derived fibrinogen in the brain, lower cortical neuron numbers, and behavioral deficits in mice. Soluble HFE2 competes with its homologue RGMa for binding to Neogenin, thereby blocking RGMa-induced downregulation of PDGF-B and Claudin-5 in endothelial cells, triggering BCB-disruption. HFE2 administration in female mice with experimental autoimmune encephalomyelitis, a model for multiple sclerosis, prevented paralysis and immune cell infiltration by inhibiting RGMa-mediated BCB alteration. This study has implications for the pathogenesis and potential treatment of diseases associated with BCB-dysfunction.

Suggested Citation

  • Xue Fan Wang & Robin Vigouroux & Michal Syonov & Yuriy Baglaenko & Angeliki M. Nikolakopoulou & Dene Ringuette & Horea Rus & Peter V. DiStefano & Suzie Dufour & Alireza P. Shabanzadeh & Seunggi Lee & , 2024. "The liver and muscle secreted HFE2-protein maintains central nervous system blood vessel integrity," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45303-1
    DOI: 10.1038/s41467-024-45303-1
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    References listed on IDEAS

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