Netrin 1 regulates blood-brain barrier function and neuroinflammation

Cornelia Podjaski, Jorge I Alvarez, Lyne Bourbonniere, Sandra Larouche, Simone Terouz, Jenea M Bin, Marc-André Lécuyer, Olivia Saint-Laurent, Catherine Larochelle, Peter J Darlington, Nathalie Arbour, Jack P Antel, Timothy E Kennedy, Alexandre Prat

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1598-612
Number of pages15
JournalBrain
Volume138
Issue numberPt 6
DOIs
Publication statusPublished - Jun 2015

Keywords

  • Animals
  • Anti-Inflammatory Agents
  • Blood Proteins
  • Blood-Brain Barrier
  • Encephalomyelitis, Autoimmune, Experimental
  • Endothelial Cells
  • Humans
  • Inflammation
  • Inflammation Mediators
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Multiple Sclerosis
  • Nerve Growth Factors
  • Permeability
  • Primary Cell Culture
  • Tight Junctions
  • Tumor Suppressor Proteins
  • Up-Regulation

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