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Rôle des rétrovirus endogènes humains dans l'inflammation de l'endothélium vasculaire

Abstract : The MSRV (Multiple Sclerosis Associated Retro Virus) belongs to the human endogenous retrovirus HERV-W family. An envelope protein originating from the MSRV was found in most patients with multiple sclerosis (MS). This protein (Env-ms) has pro-inflammatory properties on several immune cells and could therefore play a role in the 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 have demonstrated that the recombinant MSRV envelope was able to strongly stimulate several inflammatory parameters on a human BBB in vitro model, the HCMEC/D3 cell line. Indeed, Env-ms induced overexpression of ICAM-1, a major mediator of leukocyte adhesion to endothelial cells, in a dose-dependent manner and a strong dose-dependent production of the pro-inflammatory cytokines IL-6 and IL-8. Furthermore, using a silencing approach with siRNAs, we have shown that Env-ms was recognized via the TLR4 receptor, a pattern recognition receptor of innate immunity present on endothelial cells. Indeed, the knock down of TLR4 abolishes the pro-inflammatory effects of Env-ms. We have also shown using functionnal assays, that the treatment of brain endothelial cells with Env-ms significantly stimulated the adhesion of activated immune cells to the monolayer of endothelial cells. We also assessed the effects of Env-ms on primary endothelial cells HUVECs and we observed that the pro-inflammatory properties of the envelope protein were similar to those observed on HCMEC/D3. 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. The MSRV could also play a role in other chronic inflammatory diseases.
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Delphin Barbe. Rôle des rétrovirus endogènes humains dans l'inflammation de l'endothélium vasculaire. Sciences agricoles. Université de Grenoble, 2012. Français. ⟨NNT : 2012GRENV038⟩. ⟨tel-00858884⟩

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