title: Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis.
abstract: Disruption of the blood-brain barrier (BBB) is a defining and early feature of multiple sclerosis (MS) that directly damages the central nervous system (CNS), promotes immune cell infiltration, and influences clinical outcomes. There is an urgent need for new therapies to protect and restore BBB function, either by strengthening endothelial tight junctions or suppressing endothelial vesicular transcytosis. Although wingless integrated MMTV (Wnt)/β-catenin signaling plays an essential role in BBB formation and maintenance in healthy CNS, its role in BBB repair in neurologic diseases such as MS remains unclear. Using a Wnt/β-catenin reporter mouse and several downstream targets, we demonstrate that the Wnt/β-catenin pathway is up-regulated in CNS endothelial cells in both human MS and the mouse model experimental autoimmune encephalomyelitis (EAE). Increased Wnt/β-catenin activity in CNS blood vessels during EAE progression correlates with up-regulation of neuronal Wnt3 expression, as well as breakdown of endothelial cell junctions. Genetic inhibition of the Wnt/β-catenin pathway in CNS endothelium before disease onset exacerbates the clinical presentation of EAE, CD4+T-cell infiltration into the CNS, and demyelination by increasing expression of vascular cell adhesion molecule-1 and the transcytosis protein Caveolin-1 and promoting endothelial transcytosis. However, Wnt signaling attenuation does not affect the progressive degradation of tight junction proteins or paracellular BBB leakage. These results suggest that reactivation of Wnt/β-catenin signaling in CNS vessels during EAE/MS partially restores functional BBB integrity and limits immune cell infiltration into the CNS.
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, CA 92697.
authors.forename: Justin E
authors.initials: JE
authors.lastname: Lengfeld
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY 10032; da191@cumc.columbia.edu sl4151@cumc.columbia.edu.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Lutz
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY 10032.
authors.forename: Julian R
authors.initials: JR
authors.lastname: Smith
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY 10032.
authors.forename: Claudiu
authors.initials: C
authors.lastname: Diaconu
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, CA 92697.
authors.forename: Cameron
authors.initials: C
authors.lastname: Scott
authors.affiliation: Department of Medicine, Columbia University Medical Center, New York, NY 10032.
authors.forename: Sigal B
authors.initials: SB
authors.lastname: Kofman
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, NY 10032.
authors.forename: Claire
authors.initials: C
authors.lastname: Choi
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Walsh
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461.
authors.forename: Cedric S
authors.initials: CS
authors.lastname: Raine
authors.affiliation: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461.
authors.forename: Ilir
authors.initials: I
authors.lastname: Agalliu
authors.affiliation: Department of Developmental and Cell Biology, University of California, Irvine, CA 92697; da191@cumc.columbia.edu sl4151@cumc.columbia.edu.|Department of Neurology, Columbia University Medical Center, New York, NY 10032.|Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032.|Department of Pharmacology, Columbia University Medical Center, New York, NY 10032.
authors.forename: Dritan
authors.initials: D
authors.lastname: Agalliu
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D051242:Caveolin 1 / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000235:genetics / Q000378:metabolism*; D057900:Transcytosis; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D051242:Caveolin 1; D051176:beta Catenin
keywords: EAE; MS; Wnt/β-catenin signaling; blood–brain barrier; endothelial cell