| Blockade of the kinin receptor B1 protects from autoimmune CNS disease by reducing leukocyte trafficking. | |
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MedLine Citation:
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PMID: 21216565 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Disruption of the blood brain barrier (BBB) and transendothelial trafficking of immune cells into the central nervous system (CNS) are pathophysiological hallmarks of Multiple Sclerosis (MS) and its animal model, Experimental Autoimmune Encephalomyelitis (EAE). Kinins are proinflammatory peptides which are released during tissue injury including EAE. They increase vascular permeability and enhance inflammation by acting on distinct bradykinin receptors, B1R and B2R. We studied the expression of B1R and B2R and the effect of their inhibition on the disease course, BBB integrity and T cell migration following myelin oligodendrocyte glycoprotein (MOG(35-55))-induced EAE. B1R, but not B2R expression was markedly enhanced in inflammatory CNS lesions in mice and humans. Brain endothelial cells could be identified as major source of B1R protein. The severity of EAE was significantly alleviated in B1R(-/-) mice compared with wild-type (WT) controls (P<0.05). Treatment of WT mice with the B1R antagonist R715 before and after disease onset was equally effective (P<0.05) while B1R activation by R838 promoted EAE (P<0.05). B1R inhibition was accompanied by a remarkable reduction of BBB disruption and tissue inflammation. In vitro analyses revealed that B1R suppression reverses the upregulation of ICAM-I and VCAM-I at the inflamed BBB thereby limiting T cell transmigration. In contrast, blocking B2R had no significant impact on EAE. We conclude that B1R inhibition can reduce BBB damage and cell invasion during autoimmune CNS disease and may offer a novel anti-inflammatory strategy for the treatment of MS. |
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Authors:
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Kerstin Göbel; Susann Pankratz; Tilman Schneider-Hohendorf; Stefan Bittner; Michael K Schuhmann; Harald F Langer; Guido Stoll; Heinz Wiendl; Christoph Kleinschnitz; Sven G Meuth |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2011-01-08 |
Journal Detail:
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Title: Journal of autoimmunity Volume: 36 ISSN: 1095-9157 ISO Abbreviation: J. Autoimmun. Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-02-28 Completed Date: 2011-07-22 Revised Date: 2011-08-23 |
Medline Journal Info:
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Nlm Unique ID: 8812164 Medline TA: J Autoimmun Country: England |
Other Details:
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Languages: eng Pagination: 106-14 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier Ltd. All rights reserved. |
Affiliation:
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Department of Neurology, University of Wuerzburg, Josef-Schneider-Strasse 11, 97080 Wuerzburg, Germany. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Blood-Brain Barrier / drug effects, metabolism, pathology Bradykinin / analogs & derivatives, pharmacology Brain / metabolism, pathology Cell Movement / drug effects Cells, Cultured Encephalomyelitis, Autoimmune, Experimental / genetics, immunology, metabolism* Endothelial Cells / cytology, drug effects, metabolism Female Gene Expression / drug effects Humans Immunohistochemistry Leukocytes / immunology, metabolism*, pathology Male Mice Mice, Inbred C57BL Mice, Knockout Multiple Sclerosis / immunology, metabolism Myelin-Associated Glycoprotein / immunology Receptor, Bradykinin B1 / antagonists & inhibitors, genetics, metabolism* Receptor, Bradykinin B2 / genetics, metabolism Reverse Transcriptase Polymerase Chain Reaction Spinal Cord / metabolism, pathology |
| Chemical | |
Reg. No./Substance:
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0/Myelin-Associated Glycoprotein; 0/R 715; 0/Receptor, Bradykinin B1; 0/Receptor, Bradykinin B2; 0/myelin oligodendrocyte glycoprotein; 58-82-2/Bradykinin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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