Int Immunol. 2015 May 8. pii: dxv025. [Epub ahead of print]
Inflammatory response of endothelial cells to a human endogenous retrovirus associated withmultiple sclerosis is mediated by TLR4.
Duperray A, Barbe D, Raguenez G, Weksler BB, Romero IA, Couraud PO, Perron H, Marche PN.
The MSRV (Multiple Sclerosis Associated Retro Virus) 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 overexpression 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 TLR4 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.
The cause of MS has long been debated in the scientific and clinical arena. The popular held hypothesis til now has been that circulating immune cells in the blood cross into the brain via the blood-brain barrier (BBB) setting off a chain of events that results in demyelination, axonal loss etc.
The discovery of the retroviral element MSRV in the cerebrospinal fluid of an MS patient challenges this view. Several lines of investigation (outlined in the abstract above) now indicate that MSRV and its envelope protein (Env-ms) can trigger/activate inflammatory cells across the BBB, i.e. MS is a disease from within the brain.
The recruitment of activated immune cells across the BBB endothelial cells is the critical step in triggering inflammation and the course of MS.
The investigators point out that Env-ms acts as a superantigen and activates the vascular BBB endothelium and the innate immunity (circulating monocytes, microglial, dendritic cells etc.) via the TLR4/CD14 pathway leading to inflammation in the brain (see figure below).
I say let the debate begin...But on a more ergonomic route I'm sure some biotechnologist/pharmacologist can come up with a way of interfering with the Env-ms/TLR4 pathway, say a specific anti-Env-ms neutralizing antibody??!
Schematic representation of the effects of Env-ms: 1) In the blood Env-ms (ENV) can activate circulating monocytes, macrophages and dendritic cells, but also vascular endothelial cells leading to the production of pro-inflammatory cytokines (IL-6, IL-8 etc.), enhancing the adhesion of circulating cells to the endothelium and their migration through the BBB and into the brain; 2) ENV in the brain provokes activation of macrophages, microglial and dendritic cells which orient Th1 response of T cells; 3) in parallel ENV interferes with oligodendrocyte cells in activating their precursors to produce pro-inflammatory cytokines and in reducing their capacity to build myelin sheaths.
Labels: anti-Env-ms neutralizing antibody, BBB, causation, Env-ms, HERV, innate immunity, TLR4