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

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
03 Feb 2024
Historique:
received: 15 09 2022
accepted: 19 01 2024
medline: 4 2 2024
pubmed: 4 2 2024
entrez: 3 2 2024
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-024-45303-1 PMID: 38310100
pubmed: 38310100
doi: 10.1038/s41467-024-45303-1
pii: 10.1038/s41467-024-45303-1
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

1037

Subventions

Organisme : Heart and Stroke Foundation of Canada (Heart and Stroke Foundation)
ID : NA7067
Organisme : Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)
ID : PJT 162094

Informations de copyright

© 2024. The Author(s).

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Auteurs

Xue Fan Wang (XF)

Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard St.,, Toronto, M5T 2O8, ON, Canada.
Institute of Biomedical and Biomaterial Engineering, University of Toronto, 1 King's College circle,, Toronto, M5S 1A8, ON, Canada.

Robin Vigouroux (R)

Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard St.,, Toronto, M5T 2O8, ON, Canada.
Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College circle,, Toronto, M5S 1A8, ON, Canada.
ORCID: 0000-0002-3217-895X

Michal Syonov (M)

Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard St.,, Toronto, M5T 2O8, ON, Canada.
Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College circle,, Toronto, M5S 1A8, ON, Canada.

Yuriy Baglaenko (Y)

Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard St.,, Toronto, M5T 2O8, ON, Canada.

Angeliki M Nikolakopoulou (AM)

Department of Physiology and Neuroscience, The Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.

Dene Ringuette (D)

Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard St.,, Toronto, M5T 2O8, ON, Canada.
Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College circle,, Toronto, M5S 1A8, ON, Canada.

Horea Rus (H)

University of Maryland, School of Medicine, Department of Neurology, Baltimore, MD, 21201, USA.
ORCID: 0000-0003-2415-5130

Peter V DiStefano (PV)

Toronto General Hospital Research Institute, University Health Network, 101 College St. Rm 3-308, Toronto, M5L 1L7, ON, Canada.

Suzie Dufour (S)

Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard St.,, Toronto, M5T 2O8, ON, Canada.

Alireza P Shabanzadeh (AP)

Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard St.,, Toronto, M5T 2O8, ON, Canada.

Seunggi Lee (S)

Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard St.,, Toronto, M5T 2O8, ON, Canada.
Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College circle,, Toronto, M5S 1A8, ON, Canada.

Bernhard K Mueller (BK)

BioNTech resano GmbH, An der Goldgrube 12,, 55131, Mainz, Germany.

Jason Charish (J)

Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard St.,, Toronto, M5T 2O8, ON, Canada.
Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College circle,, Toronto, M5S 1A8, ON, Canada.

Hidekiyo Harada (H)

Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard St.,, Toronto, M5T 2O8, ON, Canada.
ORCID: 0000-0001-6758-4141

Jason E Fish (JE)

Toronto General Hospital Research Institute, University Health Network, 101 College St. Rm 3-308, Toronto, M5L 1L7, ON, Canada.
ORCID: 0000-0003-0640-7277

Joan Wither (J)

Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard St.,, Toronto, M5T 2O8, ON, Canada.

Thomas Wälchli (T)

Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard St.,, Toronto, M5T 2O8, ON, Canada.
Group of CNS Angiogenesis and Neurovascular Link, and Physician-Scientist Program, Institute for Regenerative Medicine, Neuroscience Center Zurich, and Division of Neurosurgery, University and University Hospital Zurich, Zurich, Switzerland.
Division of Neurosurgery, University Hospital Zurich, Zurich, Switzerland.
Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, University Health Network, Toronto, Canada.
ORCID: 0000-0002-8961-6551

Jean-François Cloutier (JF)

The Neuro - Montreal Neurological Institute and Hospital, 3801 Rue Université, Montréal, QC, H3A 2B4, Canada.
ORCID: 0000-0003-0840-2795

Berislav V Zlokovic (BV)

Department of Physiology and Neuroscience, The Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
ORCID: 0000-0002-6802-8232

Peter L Carlen (PL)

Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard St.,, Toronto, M5T 2O8, ON, Canada.
Institute of Biomedical and Biomaterial Engineering, University of Toronto, 1 King's College circle,, Toronto, M5S 1A8, ON, Canada.
Department of Physiology and Neuroscience, The Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
ORCID: 0000-0002-3339-8102

Philippe P Monnier (PP)

Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard St.,, Toronto, M5T 2O8, ON, Canada. Philippe.Monnier@uhn.ca.
Institute of Biomedical and Biomaterial Engineering, University of Toronto, 1 King's College circle,, Toronto, M5S 1A8, ON, Canada. Philippe.Monnier@uhn.ca.
Department of Ophthalmology and Vision Sciences, Faculty of Medicine, University of Toronto, 340 College St.,, ON, Toronto, M5T 3A9, Canada. Philippe.Monnier@uhn.ca.
ORCID: 0000-0002-6221-4130

Classifications MeSH