1. Adenosine A2A receptor agonist ameliorates EAE and correlates with Th1 cytokine-induced blood brain barrier dysfunction via suppression of MLCK signaling pathway.
- Author
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Liu Y, Alahiri M, Ulloa B, Xie B, and Sadiq SA
- Subjects
- Adult, Aged, Aged, 80 and over, Animals, Blood-Brain Barrier pathology, Encephalomyelitis, Autoimmune, Experimental pathology, Female, Gene Expression Regulation immunology, Humans, Male, Mice, Middle Aged, Multiple Sclerosis immunology, Multiple Sclerosis pathology, Th1 Cells pathology, Blood-Brain Barrier immunology, Cytokines immunology, Encephalomyelitis, Autoimmune, Experimental immunology, Myosin-Light-Chain Kinase immunology, Receptor, Adenosine A2A immunology, Signal Transduction immunology, Th1 Cells immunology
- Abstract
Introduction: Multiple sclerosis (MS) disease activity is associated with blood-brain barrier (BBB) disruption, which is mediated by inflammatory cytokines released by CD4+ lymphocytes. To assess the effects of adenosine A2A receptors on BBB permeability in vitro and in vivo., Methods: A2A receptor expression was detected by immunostaining in experimental autoimmune encephalomyelitis (EAE) C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein (MOG)
35-55 , and human MS brain. F-actin and the tight junction protein Claudin-5 were assessed in endothelial cells treated with an A2A receptor specific agonist (CGS-21680) after Th1 cytokine stimulation. EAE mice were divided into control and CGS-21680 (50 µg/kg, i.p., daily) groups. Disease scores were recorded daily to evaluate neurological impairment. The effects of A2A receptor on inflammation and demyelination were assessed after euthanasia by immunostaining or histology; BBB permeability was measured by sodium fluoride (Na-F) and FITC-dextran amounts., Results: Endothelial A2A receptor was detected in demyelination areas of MS brain samples. In EAE lesions, A2A receptor was expressed in the endothelium in association with immune cell infiltration. Treatment with CGS-21680 counteracted the effects of Th1 cytokines on endothelial cells in vitro, preventing the reduction of tight junction protein expression and stress fiber formation. The effects of A2A receptor activation were correlated with MLCK phosphorylation signaling repression. In EAE, A2A receptor agonist decreased BBB permeability and inhibited EAE neurologic deficiency in mice., Conclusions: A2A receptor activation at EAE onset helps reduce the effects of Th1 stimulation on BBB permeability, indicating that A2A receptor mediates BBB function in CNS demyelinated disease., (© 2017 The Authors. Immunity, Inflammation and Disease Published by John Wiley & Sons Ltd.)- Published
- 2018
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