title: Identification of an essential endogenous regulator of blood-brain barrier integrity, and its pathological and therapeutic implications.
abstract: The blood-brain barrier (BBB), a critical guardian of communication between the periphery and the brain, is frequently compromised in neurological diseases such as multiple sclerosis (MS), resulting in the inappropriate passage of molecules and leukocytes into the brain. Here we show that the glucocorticoid anti-inflammatory messenger annexin A1 (ANXA1) is expressed in brain microvascular endothelial cells, where it regulates BBB integrity. In particular, ANXA1(-/-) mice exhibit significantly increased BBB permeability as a result of disrupted interendothelial cell tight junctions, essentially related to changes in the actin cytoskeleton, which stabilizes tight and adherens junctions. This situation is reminiscent of early MS pathology, a relationship confirmed by our detection of a selective loss of ANXA1 in the plasma and cerebrovascular endothelium of patients with MS. Importantly, this loss is swiftly restored by i.v. administration of human recombinant ANXA1. Analysis in vitro confirms that treatment of cerebrovascular endothelial cells with recombinant ANXA1 restores cell polarity, cytoskeleton integrity, and paracellular permeability through inhibition of the small G protein RhoA. We thus propose ANXA1 as a critical physiological regulator of BBB integrity and suggest it may have utility in the treatment of MS, correcting BBB function and hence ameliorating disease.
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry,  Queen Mary University of London, London EC1M 6BQ,  United Kingdom.
authors.forename: Enrico
authors.initials: E
authors.lastname: Cristante
authors.forename: Simon
authors.initials: S
authors.lastname: McArthur
authors.forename: Claudio
authors.initials: C
authors.lastname: Mauro
authors.forename: Elisa
authors.initials: E
authors.lastname: Maggioli
authors.forename: Ignacio A
authors.initials: IA
authors.lastname: Romero
authors.forename: Marzena
authors.initials: M
authors.lastname: Wylezinska-Arridge
authors.forename: Pierre O
authors.initials: PO
authors.lastname: Couraud
authors.forename: Jordi
authors.initials: J
authors.lastname: Lopez-Tremoleda
authors.forename: Helen C
authors.initials: HC
authors.lastname: Christian
authors.forename: Babette B
authors.initials: BB
authors.lastname: Weksler
authors.forename: Andrea
authors.initials: A
authors.lastname: Malaspina
authors.forename: Egle
authors.initials: E
authors.lastname: Solito
mesh_terms: D008841:Actin Cytoskeleton / Q000502:physiology; D022005:Adherens Junctions / Q000473:pathology / Q000502:physiology; D000328:Adult; D000368:Aged; D000818:Animals; D017305:Annexin A1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D001812:Blood-Brain Barrier / Q000473:pathology / Q000502:physiology* / Q000503:physiopathology; D002199:Capillary Permeability / Q000502:physiology; D002460:Cell Line; D042783:Endothelial Cells / Q000473:pathology / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055806:Microvessels / Q000473:pathology / Q000503:physiopathology; D008875:Middle Aged; D008959:Models, Neurological; D009103:Multiple Sclerosis / Q000473:pathology / Q000503:physiopathology; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D062725:Tight Junction Proteins / Q000502:physiology; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D017305:Annexin A1; D011994:Recombinant Proteins; D062725:Tight Junction Proteins; C573274:annexin A1, mouse; C066737:RHOA protein, human; D020742:rhoA GTP-Binding Protein