| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Nature Communications, Vol 15, Iss 1, Pp 1-16 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2041-1723 |
| DOI: |
10.1038/s41467-024-45303-1 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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