title: The Hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence.
abstract: The blood-brain barrier (BBB) is composed of tightly bound endothelial cells (ECs) and perivascular astrocytes that regulate central nervous system (CNS) homeostasis. We showed that astrocytes secrete Sonic hedgehog and that BBB ECs express Hedgehog (Hh) receptors, which together promote BBB formation and integrity during embryonic development and adulthood. Using pharmacological inhibition and genetic inactivation of the Hh signaling pathway in ECs, we also demonstrated a critical role of the Hh pathway in promoting the immune quiescence of BBB ECs by decreasing the expression of proinflammatory mediators and the adhesion and migration of leukocytes, in vivo and in vitro. Overall, the Hh pathway provides a barrier-promoting effect and an endogenous anti-inflammatory balance to CNS-directed immune attacks, as occurs in multiple sclerosis.
authors.affiliation: Neuroimmunology Unit, Center of Excellence in Neuromics, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Faculty of Medicine, Université de Montréal, Montréal, Quebec, Canada.
authors.forename: Jorge Ivan
authors.initials: JI
authors.lastname: Alvarez
authors.forename: Aurore
authors.initials: A
authors.lastname: Dodelet-Devillers
authors.forename: Hania
authors.initials: H
authors.lastname: Kebir
authors.forename: Igal
authors.initials: I
authors.lastname: Ifergan
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Fabre
authors.forename: Simone
authors.initials: S
authors.lastname: Terouz
authors.forename: Mike
authors.initials: M
authors.lastname: Sabbagh
authors.forename: Karolina
authors.initials: K
authors.lastname: Wosik
authors.forename: Lyne
authors.initials: L
authors.lastname: Bourbonnière
authors.forename: Monique
authors.initials: M
authors.lastname: Bernard
authors.forename: Jack
authors.initials: J
authors.lastname: van Horssen
authors.forename: Helga E
authors.initials: HE
authors.lastname: de Vries
authors.forename: Frédéric
authors.initials: F
authors.lastname: Charron
authors.forename: Alexandre
authors.initials: A
authors.lastname: Prat
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000166:cytology / Q000502:physiology*; D001921:Brain / Q000276:immunology* / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D017097:Electric Impedance; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000276:immunology / Q000378:metabolism; D010539:Permeability; D015398:Signal Transduction; D014704:Veratrum Alkaloids / Q000494:pharmacology
chemical_list: D018925:Chemokines; D053823:Hedgehog Proteins; D018836:Inflammation Mediators; C509239:SHH protein, human; C465570:Shh protein, mouse; D014704:Veratrum Alkaloids; C000541:cyclopamine