title: Netrin 1 regulates blood-brain barrier function and neuroinflammation.
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.
authors.affiliation: 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.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Podjaski
authors.affiliation: 1 Neuroimmunology Unit, Department of Neuroscience, Centre de Recherche du CHUM (CRCHUM), Université de Montréal, Montréal, Québec, Canada.
authors.forename: Jorge I
authors.initials: JI
authors.lastname: Alvarez
authors.affiliation: 1 Neuroimmunology Unit, Department of Neuroscience, Centre de Recherche du CHUM (CRCHUM), Université de Montréal, Montréal, Québec, Canada.
authors.forename: Lyne
authors.initials: L
authors.lastname: Bourbonniere
authors.affiliation: 1 Neuroimmunology Unit, Department of Neuroscience, Centre de Recherche du CHUM (CRCHUM), Université de Montréal, Montréal, Québec, Canada.
authors.forename: Sandra
authors.initials: S
authors.lastname: Larouche
authors.affiliation: 1 Neuroimmunology Unit, Department of Neuroscience, Centre de Recherche du CHUM (CRCHUM), Université de Montréal, Montréal, Québec, Canada.
authors.forename: Simone
authors.initials: S
authors.lastname: Terouz
authors.affiliation: 2 Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, Québec, Canada.
authors.forename: Jenea M
authors.initials: JM
authors.lastname: Bin
authors.affiliation: 1 Neuroimmunology Unit, Department of Neuroscience, Centre de Recherche du CHUM (CRCHUM), Université de Montréal, Montréal, Québec, Canada.
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Lécuyer
authors.affiliation: 1 Neuroimmunology Unit, Department of Neuroscience, Centre de Recherche du CHUM (CRCHUM), Université de Montréal, Montréal, Québec, Canada.
authors.forename: Olivia
authors.initials: O
authors.lastname: Saint-Laurent
authors.affiliation: 1 Neuroimmunology Unit, Department of Neuroscience, Centre de Recherche du CHUM (CRCHUM), Université de Montréal, Montréal, Québec, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Larochelle
authors.affiliation: 2 Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, Québec, Canada.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Darlington
authors.affiliation: 1 Neuroimmunology Unit, Department of Neuroscience, Centre de Recherche du CHUM (CRCHUM), Université de Montréal, Montréal, Québec, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Arbour
authors.affiliation: 2 Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, Québec, Canada.
authors.forename: Jack P
authors.initials: JP
authors.lastname: Antel
authors.affiliation: 2 Department of Neurology and Neurosurgery, Montréal Neurological Institute, McGill University, Montréal, Québec, Canada.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Kennedy
authors.affiliation: 1 Neuroimmunology Unit, Department of Neuroscience, Centre de Recherche du CHUM (CRCHUM), Université de Montréal, Montréal, Québec, Canada a.prat@umontreal.ca.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Prat
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D001798:Blood Proteins / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use*; D000075388:Netrin-1; D010539:Permeability; D061251:Primary Cell Culture; D019108:Tight Junctions / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use*; D015854:Up-Regulation
chemical_list: D000893:Anti-Inflammatory Agents; D001798:Blood Proteins; D018836:Inflammation Mediators; D008565:Membrane Proteins; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1
keywords: blood–brain barrier; experimental autoimmune encephalomyelitis; multiple sclerosis; netrin 1; neuroinflammation