期刊
BRAIN
卷 138, 期 -, 页码 1598-1612出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awv092
关键词
multiple sclerosis; experimental autoimmune encephalomyelitis; blood-brain barrier; netrin 1; neuroinflammation
资金
- Canadian Institutes of Health Research (CIHR) [MOP81880]
- Multiple Sclerosis Society of Canada (MSSC)
- CIHR
- MSSC
- Fonds de Recherche du Quebecsante
- Killam Foundation Scholar award
Blood-brain barrier function is driven by the influence of astrocyte-secreted factors. During neuroinflammatory responses the blood-brain barrier is compromised resulting in central nervous system damage and exacerbated pathology. Here, we identified endothelial netrin 1 induction as a vascular response to astrocyte-derived sonic hedgehog that promotes autocrine barrier properties during homeostasis and increases with inflammation. Netrin 1 supports blood-brain barrier integrity by upregulating endothelial junctional protein expression, while netrin 1 knockout mice display disorganized tight junction protein expression and barrier breakdown. Upon inflammatory conditions, blood-brain barrier endothelial cells significantly upregulated netrin 1 levels in vitro and in situ, which prevented junctional breach and endothelial cell activation. Finally, netrin 1 treatment during experimental autoimmune encephalomyelitis significantly reduced blood-brain barrier disruption and decreased clinical and pathological indices of disease severity. Our results demonstrate that netrin 1 is an important regulator of blood-brain barrier maintenance that protects the central nervous system against inflammatory conditions such as multiple sclerosis and experimental autoimmune encephalomyelitis.
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