Identification of an essential endogenous regulator of blood–brain barrier integrity, and its pathological and therapeutic implications
Identifieur interne : 001123 ( Main/Exploration ); 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
Affiliations:
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Le document en format XML
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<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>
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