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; Philippe P Monnier

doi:10.1038/s41467-024-45303-1

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

Nat Commun. 2024 Feb 3;15(1):1037. doi: 10.1038/s41467-024-45303-1.

Authors

Xue Fan Wang^#^{1

2}, Robin Vigouroux^#^{1

3}, Michal Syonov^#^{1

3}, Yuriy Baglaenko¹, Angeliki M Nikolakopoulou⁴, Dene Ringuette^{1

3}, Horea Rus⁵, Peter V DiStefano⁶, Suzie Dufour¹, Alireza P Shabanzadeh¹, Seunggi Lee^{1

3}, Bernhard K Mueller⁷, Jason Charish^{1

3}, Hidekiyo Harada¹, Jason E Fish⁶, Joan Wither¹, Thomas Wälchli^{1

8

9

10}, Jean-François Cloutier¹¹, Berislav V Zlokovic⁴, Peter L Carlen^{1

2

4}, Philippe P Monnier^{12

13

14}

Affiliations

¹ Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard St.,, Toronto, M5T 2O8, ON, Canada.
² Institute of Biomedical and Biomaterial Engineering, University of Toronto, 1 King's College circle,, Toronto, M5S 1A8, ON, Canada.
³ Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College circle,, Toronto, M5S 1A8, ON, Canada.
⁴ Department of Physiology and Neuroscience, The Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
⁵ University of Maryland, School of Medicine, Department of Neurology, Baltimore, MD, 21201, USA.
⁶ Toronto General Hospital Research Institute, University Health Network, 101 College St. Rm 3-308, Toronto, M5L 1L7, ON, Canada.
⁷ BioNTech resano GmbH, An der Goldgrube 12,, 55131, Mainz, Germany.
⁸ 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.
⁹ Division of Neurosurgery, University Hospital Zurich, Zurich, Switzerland.
¹⁰ Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, University Health Network, Toronto, Canada.
¹¹ The Neuro - Montreal Neurological Institute and Hospital, 3801 Rue Université, Montréal, QC, H3A 2B4, Canada.
¹² Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard St.,, Toronto, M5T 2O8, ON, Canada. Philippe.Monnier@uhn.ca.
¹³ Institute of Biomedical and Biomaterial Engineering, University of Toronto, 1 King's College circle,, Toronto, M5S 1A8, ON, Canada. Philippe.Monnier@uhn.ca.
¹⁴ Department of Ophthalmology and Vision Sciences, Faculty of Medicine, University of Toronto, 340 College St.,, ON, Toronto, M5T 3A9, Canada. Philippe.Monnier@uhn.ca.

^# Contributed equally.

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.

MeSH terms

Animals
Blood-Brain Barrier* / metabolism
Central Nervous System / metabolism
Encephalomyelitis, Autoimmune, Experimental*
Endothelial Cells / metabolism
Female
Liver / metabolism
Mice
Muscles / metabolism

Substances

HJV protein, mouse

Abstract

MeSH terms

Substances

Grants and funding