pHERV-W envelope protein fuels microglial cell-dependent damage of myelinated axons in multiple sclerosis

Abstract

Axonal degeneration is central to clinical disability and disease progression in multiple sclerosis (MS). Myeloid cells such as brain-resident microglia and blood-borne monocytes are thought to be critically involved in this degenerative process. However, the exact underlying mechanisms have still not been clarified. We have previously demonstrated that human endogenous retrovirus type W (HERV-W) negatively affects oligodendroglial precursor cell (OPC) differentiation and remyelination via its envelope protein pathogenic HERV-W (pHERV-W) ENV (formerly MS-associated retrovirus [MSRV]-ENV). In this current study, we investigated whether pHERV-W ENV also plays a role in axonal injury in MS. We found that in MS lesions, pHERV-W ENV is present in myeloid cells associated with axons. Focusing on progressive disease stages, we could then demonstrate that pHERV-W ENV induces a degenerative phenotype in microglial cells, driving them toward a close spatial association with myelinated axons. Moreover, in pHERV-W ENV-stimulated myelinated cocultures, microglia were found to structurally damage myelinated axons. Taken together, our data suggest that pHERV-W ENV-mediated microglial polarization contributes to neurodegeneration in MS. Thus, this analysis provides a neurobiological rationale for a recently completed clinical study in MS patients showing that antibody-mediated neutralization of pHERV-W ENV exerts neuroprotective effects.

Increased Serological Response Against Human Herpesvirus 6A Is Associated With Risk for Multiple Sclerosis

“…Similar interaction with HLA has previously been reported for immune response to EBV (19). How these interactions fit with the previously suggested mechanisms for how viruses can trigger autoimmunity, like molecular mimicry and bystander activation (55,56), as well as interactions with other viruses not studied here (57,58), remains to be determined and the present study adds to the complexity regarding the specificity explained by these mechanisms.…”

Human retrovirus pHEV-W envelope protein and the pathogenesis of multiple sclerosis

“…It appears that, if a human retrovirus is involved, it is more likely to be through activation of retroviral genes that have been incorporated into the human genome (7,11,12). The current study by Kremer et al (13) in PNAS is important, for it does not just look at the association of pHERV-W envelope protein and MS but also examines potential mechanisms by which the protein causes axonal damage in MS. Axonal damage in white matter and loss of neurons/axons in cortical and deep gray matter are major determinants of disability in MS (14-16).…”

“…If pHERV-W envelope protein expression is specifically associated with MS, are other viruses associated with these other disorders in which there is also microglial activation, presumably in response to a "sick" neuron or OL in the neighborhood? Kremer et al (13) point out the role of toll-like receptor 4 (TLR4) in pHEV-W activation of microglia, and there are other TLRs and other nonantigen-specific molecules expressed in response to "danger" signals. Along with astrocytes (28,29), microglia interactions with neurons and OL (27,30) are instrumental in pathogenesis and protection/repair in the CNS (31)(32)(33).…”

HERV and Epstein-Barr Virus: Another Piece to Multiple Sclerosis Puzzle

“…After Toll Like Receptor 4 (TLR 4) recognition, HERV-W env can activate innate immune response, especially macrophages and microglia, resulting in major inflammation [Arneth 2018;Bahrami 2018;Grandi 2018;Kremer et al 2019]. HERVs mostly leads to M1 macrophages stimulation, the proinflammatory phenotype; more than the antiinflammatory ones, M2 [Arneth 2018.…”

“…HERVs mostly leads to M1 macrophages stimulation, the proinflammatory phenotype; more than the antiinflammatory ones, M2 [Arneth 2018. M1 macrophages leads to reactive oxygen, nitrogen species and inflammatory cytokines release, and microglia cells also produce proinflammatory molecules [Kremer et al 2019]. Dendritic cells are also activated Greening 2019].…”