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The liver and muscle secreted HFE2-protein maintains central nervous system blood vessel integrity.
Wang, Xue Fan; Vigouroux, Robin; Syonov, Michal; Baglaenko, Yuriy; Nikolakopoulou, Angeliki M; Ringuette, Dene; Rus, Horea; DiStefano, Peter V; Dufour, Suzie; Shabanzadeh, Alireza P; Lee, Seunggi; Mueller, Bernhard K; Charish, Jason; Harada, Hidekiyo; Fish, Jason E; Wither, Joan; Wälchli, Thomas; Cloutier, Jean-François; Zlokovic, Berislav V; Carlen, Peter L; Monnier, Philippe P.
Afiliação
  • Wang XF; Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard St.,, Toronto, M5T 2O8, ON, Canada.
  • Vigouroux R; Institute of Biomedical and Biomaterial Engineering, University of Toronto, 1 King's College circle,, Toronto, M5S 1A8, ON, Canada.
  • Syonov M; Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard St.,, Toronto, M5T 2O8, ON, Canada.
  • Baglaenko Y; Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College circle,, Toronto, M5S 1A8, ON, Canada.
  • Nikolakopoulou AM; Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard St.,, Toronto, M5T 2O8, ON, Canada.
  • Ringuette D; Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College circle,, Toronto, M5S 1A8, ON, Canada.
  • Rus H; Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard St.,, Toronto, M5T 2O8, ON, Canada.
  • DiStefano PV; Department of Physiology and Neuroscience, The Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
  • Dufour S; Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard St.,, Toronto, M5T 2O8, ON, Canada.
  • Shabanzadeh AP; Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College circle,, Toronto, M5S 1A8, ON, Canada.
  • Lee S; University of Maryland, School of Medicine, Department of Neurology, Baltimore, MD, 21201, USA.
  • Mueller BK; Toronto General Hospital Research Institute, University Health Network, 101 College St. Rm 3-308, Toronto, M5L 1L7, ON, Canada.
  • Charish J; Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard St.,, Toronto, M5T 2O8, ON, Canada.
  • Harada H; Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard St.,, Toronto, M5T 2O8, ON, Canada.
  • Fish JE; Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard St.,, Toronto, M5T 2O8, ON, Canada.
  • Wither J; Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College circle,, Toronto, M5S 1A8, ON, Canada.
  • Wälchli T; BioNTech resano GmbH, An der Goldgrube 12,, 55131, Mainz, Germany.
  • Cloutier JF; Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard St.,, Toronto, M5T 2O8, ON, Canada.
  • Zlokovic BV; Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College circle,, Toronto, M5S 1A8, ON, Canada.
  • Carlen PL; Krembil Research Institute, University Health Network, Krembil Discovery Tower, 60 Leonard St.,, Toronto, M5T 2O8, ON, Canada.
  • Monnier PP; Toronto General Hospital Research Institute, University Health Network, 101 College St. Rm 3-308, Toronto, M5L 1L7, ON, Canada.
Nat Commun ; 15(1): 1037, 2024 Feb 03.
Article em En | MEDLINE | ID: mdl-38310100
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Barreira Hematoencefálica / Encefalomielite Autoimune Experimental Limite: Animals Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Canadá
Texto completo
Imprimir
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Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Barreira Hematoencefálica / Encefalomielite Autoimune Experimental Limite: Animals Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Canadá