title: Inflammatory response of endothelial cells to a human endogenous retrovirus associated with multiple sclerosis is mediated by TLR4.
abstract: The MSRV (multiple sclerosis-associated retrovirus) belongs to the human endogenous retrovirus HERV-W family. The envelope protein originating from the MSRV has been found in most patients with multiple sclerosis (MS). This protein (Env-ms) has pro-inflammatory properties for several types of immune cells and could therefore play a role in MS pathogenesis by promoting the leukocyte diapedesis observed in the central nervous system of patients. Our study aims to analyze the effects of Env-ms on the blood-brain barrier (BBB) at a molecular and functional level. We demonstrate that the recombinant MSRV envelope is able to stimulate several inflammatory parameters in a human BBB in vitro model, the HCMEC/D3 brain endothelial cell line. Indeed, Env-ms induces over-expression of ICAM-1, a major mediator of leukocyte adhesion to endothelial cells, in a dose-dependent manner as well as a strong dose-dependent production of the pro-inflammatory cytokines IL-6 and IL-8. Furthermore, using a silencing approach with siRNAs, we show that Env-ms is recognized via the Toll-like receptor 4 receptor, a pattern recognition receptor of innate immunity present on endothelial cells. We also show, using functional assays, that treatment of brain endothelial cells with Env-ms significantly stimulated the adhesion and the transmigration of activated immune cells through a monolayer of endothelial cells. These findings support the hypothesis that MSRV could be involved in the pathogenesis of MS disease or at least in maintenance of inflammatory conditions, thus fueling the auto-immune disorder. MSRV could also play a role in other chronic inflammatory diseases.
authors.affiliation: INSERM U823, F-38000 Grenoble, France Université Grenoble Alpes, IAB, F-38000 Grenoble, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Duperray
authors.affiliation: INSERM U823, F-38000 Grenoble, France Université Grenoble Alpes, IAB, F-38000 Grenoble, France.
authors.forename: Delphin
authors.initials: D
authors.lastname: Barbe
authors.affiliation: INSERM U823, F-38000 Grenoble, France Université Grenoble Alpes, IAB, F-38000 Grenoble, France Present address: Centre de Recherche en Neurobiologie - Neurophysiologie de Marseille, Université de la Méditerranée Aix-Marseille 2, CNRS UMR7286, 13344 Marseille, France.
authors.forename: Gilda
authors.initials: G
authors.lastname: Raguenez
authors.affiliation: Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Babette B
authors.initials: BB
authors.lastname: Weksler
authors.affiliation: Department of Biological Sciences, The Open University, Walton Hall, Milton Keynes MK7 6BJ, UK.
authors.forename: Ignacio A
authors.initials: IA
authors.lastname: Romero
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Couraud
authors.affiliation: GeNeuro, 18, chemin des Aulx, 1228 Plan-les-Ouates, Geneva, Switzerland.
authors.forename: Hervé
authors.initials: H
authors.lastname: Perron
authors.affiliation: INSERM U823, F-38000 Grenoble, France Université Grenoble Alpes, IAB, F-38000 Grenoble, France patrice.marche@inserm.fr.
authors.forename: Patrice N
authors.initials: PN
authors.lastname: Marche
mesh_terms: D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000276:immunology / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D020077:Endogenous Retroviruses; D042783:Endothelial Cells / Q000378:metabolism* / Q000821:virology*; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D015686:Gene Products, env / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism; D009103:Multiple Sclerosis / Q000209:etiology* / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D015686:Gene Products, env; D018836:Inflammation Mediators; D051197:Toll-Like Receptor 4; D018799:Intercellular Adhesion Molecule-1
keywords: auto-immune disease; blood–brain barrier; leukocyte adhesion; retroviral envelope