Identification of an essential endogenous regulator of blood–brain barrier integrity, and its pathological and therapeutic implications
Identifieur interne : 001123 ( Main/Curation ); précédent : 001122; suivant : 001124Identification of an essential endogenous regulator of blood–brain barrier integrity, and its pathological and therapeutic implications
Auteurs : Enrico Cristante [Royaume-Uni] ; Simon Mcarthur [Royaume-Uni] ; Claudio Mauro [Royaume-Uni] ; Elisa Maggioli [Royaume-Uni] ; Ignacio A. Romero ; Marzena Wylezinska-Arridge [Royaume-Uni] ; Pierre O. Couraud [France] ; Jordi Lopez-Tremoleda [Royaume-Uni] ; Helen C. Christian [Royaume-Uni] ; Babette B. Weksler ; Andrea Malaspina [Royaume-Uni] ; Egle Solito [Royaume-Uni]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2012.
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.
Url:
DOI: 10.1073/pnas.1209362110
PubMed: 23277546
PubMed Central: 3549094
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Ignacio A. Romero<affiliation><nlm:aff id="aff2">Department of Life Sciences,<institution>The Open Universit</institution>y, Milton Keynes MK7 6AA,<country>United Kingdom;</country></nlm:aff><wicri:noCountry code="nlm country">United Kingdom;</wicri:noCountry></affiliation>Le document en format XML
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Romero</name><affiliation><nlm:aff id="aff2">Department of Life Sciences,<institution>The Open Universit</institution>y, Milton Keynes MK7 6AA,<country>United Kingdom;</country></nlm:aff><wicri:noCountry code="nlm country">United Kingdom;</wicri:noCountry></affiliation></author><author><name sortKey="Wylezinska Arridge, Marzena" sort="Wylezinska Arridge, Marzena" uniqKey="Wylezinska Arridge M" first="Marzena" last="Wylezinska-Arridge">Marzena Wylezinska-Arridge</name><affiliation wicri:level="1"><nlm:aff id="aff3">Institute of Clinical Science,<institution>Imperial College London</institution>, London W12 0NN,<country>United Kingdom</country>;</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Couraud, Pierre O" sort="Couraud, Pierre O" uniqKey="Couraud P" first="Pierre O." last="Couraud">Pierre O. Couraud</name><affiliation wicri:level="1"><nlm:aff id="aff4">INSERM U1016, Institut Cochin,<institution>Université Paris Descartes</institution>, 75014 Paris,<country>France</country>;</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lopez Tremoleda, Jordi" sort="Lopez Tremoleda, Jordi" uniqKey="Lopez Tremoleda J" first="Jordi" last="Lopez-Tremoleda">Jordi Lopez-Tremoleda</name><affiliation wicri:level="1"><nlm:aff id="aff3">Institute of Clinical Science,<institution>Imperial College London</institution>, London W12 0NN,<country>United Kingdom</country>;</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Christian, Helen C" sort="Christian, Helen C" uniqKey="Christian H" first="Helen C." last="Christian">Helen C. Christian</name><affiliation wicri:level="1"><nlm:aff id="aff5">Department of Physiology, Anatomy and Genetics,<institution>University of Oxford</institution>, Oxford OX1 3QX,<country>United Kingdom</country>;</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Weksler, Babette B" sort="Weksler, Babette B" uniqKey="Weksler B" first="Babette B." last="Weksler">Babette B. Weksler</name><affiliation><nlm:aff wicri:cut="; and" id="aff6">Division of Haematology and Medical Oncology,<institution>Weill Medical College of Cornell University</institution>, New York,<addr-line>NY</addr-line> 10065</nlm:aff></affiliation></author><author><name sortKey="Malaspina, Andrea" sort="Malaspina, Andrea" uniqKey="Malaspina A" first="Andrea" last="Malaspina">Andrea Malaspina</name><affiliation><nlm:aff wicri:cut=" and" id="aff7">North-East London and Essex MND Care and Research Centre</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="aff8">Centre for Neuroscience and Trauma, Blizard Institute,<institution>Queen Mary University of London</institution>, London E1 2AT,<country>United Kingdom</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Solito, Egle" sort="Solito, Egle" uniqKey="Solito E" first="Egle" last="Solito">Egle Solito</name><affiliation wicri:level="1"><nlm:aff id="aff1">William Harvey Research Institute, Barts and the London School of Medicine and Dentistry,<institution>Queen Mary University of London</institution>, London EC1M 6BQ,<country>United Kingdom</country>;</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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<sup>−/−</sup> 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.</p></div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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