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

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, Bernhard K. Mueller, Jason Charish, Hidekiyo Harada, Jason E. Fish, Joan Wither, Thomas Wälchli, Jean-François Cloutier, Berislav V. Zlokovic, Peter L. Carlen and Philippe P. Monnier ()
Additional contact information
Xue Fan Wang: University Health Network, Krembil Discovery Tower
Robin Vigouroux: University Health Network, Krembil Discovery Tower
Michal Syonov: University Health Network, Krembil Discovery Tower
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
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
Bernhard K. Mueller: BioNTech resano GmbH
Jason Charish: University Health Network, Krembil Discovery Tower
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
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
Philippe P. Monnier: University Health Network, Krembil Discovery Tower

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45303-1

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