| Autor: |
Angeliki M. Nikolakopoulou, Dene Ringuette, Jason Charish, Joan E. Wither, Alireza P. Shabanzadeh, Seunggi Lee, Horea Rus, Bernhard K. Mueller, Hidekiyo Harada, Jean-François Cloutier, Peter L. Carlen, Philippe P. Monnier, Peter V. DiStefano, Michal Syonov, Thomas Wälchli, Yuriy Baglaenko, Suzie Dufour, Robin J. Vigouroux, Jason E. Fish, Xue Fan Wang, Berislav V. Zlokovic |
| Rok vydání: |
2022 |
| Předmět: |
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| Popis: |
Liver failure causes blood-brain-barrier (BBB) breakdown leading to central nervous system damage, however the mechanisms whereby the liver influences BBB-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 BBB integrity. We developed light-sheet imaging for three-dimensional study of BBB function. We show that liver- or muscle-specific knockout of Hfe2 induces BBB breakdown, leading to accumulation of toxic-blood-derived fibrinogen in the brain, lower cortical neuron numbers, and behavioral deficits. In healthy animals, 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 and the ensuing BBB disruption. Hfe2 administration in an animal model of multiple sclerosis prevented paralysis and immune cell infiltration by inhibiting RGMa-mediated BBB alteration. This study has implications for the pathogenesis and potential treatment of diseases associated with BBB dysfunction such as multiple sclerosis. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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