Netrin 1 regulates blood-brain barrier function and neuroinflammation

• Published in: Brain (London, England : 1878) Vol. 138; no. Pt 6; pp. 1598 - 1612
• Main Authors: Podjaski, Cornelia, Alvarez, Jorge I, Bourbonniere, Lyne, Larouche, Sandra, Terouz, Simone, Bin, Jenea M, Lécuyer, Marc-André, Saint-Laurent, Olivia, Larochelle, Catherine, Darlington, Peter J, Arbour, Nathalie, Antel, Jack P, Kennedy, Timothy E, Prat, Alexandre
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.06.2015
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Blood Proteins - metabolism; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - metabolism; Endothelial Cells - metabolism; Humans; Inflammation - drug therapy; Inflammation - metabolism; Inflammation Mediators - metabolism; Membrane Proteins - metabolism; Mice; Mice, Knockout; Multiple Sclerosis - metabolism; Nerve Growth Factors - genetics; Nerve Growth Factors - metabolism; Nerve Growth Factors - pharmacology; Nerve Growth Factors - physiology; Nerve Growth Factors - therapeutic use; Netrin-1; Original; Permeability; Primary Cell Culture; Tight Junctions - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumor Suppressor Proteins - pharmacology; Tumor Suppressor Proteins - physiology; Tumor Suppressor Proteins - therapeutic use; Up-Regulation; blood–brain barrier; experimental autoimmune encephalomyelitis; netrin 1; neuroinflammation; multiple sclerosis
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awv092

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.