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 language | English |
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Pages (from-to) | 1598-612 |
Number of pages | 15 |
Journal | Brain |
Volume | 138 |
Issue number | Pt 6 |
DOIs | |
Publication status | Published - Jun 2015 |
Keywords / Materials (for Non-textual outputs)
- 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