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Brain. 2015 Jun;138(Pt 6):1598-612. doi: 10.1093/brain/awv092. Epub 2015 Apr 22.

Netrin 1 regulates blood-brain barrier function and neuroinflammation.

Author information

1
1 Neuroimmunology Unit, Department of Neuroscience, Centre de Recherche du CHUM (CRCHUM), Université de Montréal, Montréal, Québec, Canada 2 Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, Québec, Canada.
2
1 Neuroimmunology Unit, Department of Neuroscience, Centre de Recherche du CHUM (CRCHUM), Université de Montréal, Montréal, Québec, Canada.
3
2 Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, Québec, Canada.
4
1 Neuroimmunology Unit, Department of Neuroscience, Centre de Recherche du CHUM (CRCHUM), Université de Montréal, Montréal, Québec, Canada a.prat@umontreal.ca.

Abstract

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.

KEYWORDS:

blood–brain barrier; experimental autoimmune encephalomyelitis; multiple sclerosis; netrin 1; neuroinflammation

PMID:
25903786
PMCID:
PMC4614143
DOI:
10.1093/brain/awv092
[Indexed for MEDLINE]
Free PMC Article

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