Human endogenous retrovirus type W envelope protein inhibits oligodendroglial precursor cell differentiation
Article first published online: 16 SEP 2013
© 2013 American Neurological Association
Annals of Neurology
Volume 74, Issue 5, pages 721–732, November 2013
How to Cite
Kremer, D., Schichel, T., Förster, M., Tzekova, N., Bernard, C., van der Valk, P., van Horssen, J., Hartung, H.-P., Perron, H. and Küry, P. (2013), Human endogenous retrovirus type W envelope protein inhibits oligodendroglial precursor cell differentiation. Ann Neurol., 74: 721–732. doi: 10.1002/ana.23970
- Issue published online: 18 DEC 2013
- Article first published online: 16 SEP 2013
- Accepted manuscript online: 8 JUL 2013 02:41AM EST
- Manuscript Accepted: 28 JUN 2013
- Manuscript Revised: 20 JUN 2013
- Manuscript Received: 1 OCT 2012
Differentiation of oligodendroglial precursor cells is crucial for central nervous system remyelination and is influenced by both extrinsic and intrinsic factors. Recent studies showed that human endogenous retrovirus type W (HERV-W) contributes significantly to brain damage. In particular, its envelope protein ENV can mediate injury to specific cell types of the brain and immune system. Here, we investigated whether ENV protein affects oligodendroglial differentiation.
Immunostaining and gene expression analyses were performed to establish the expression and regulation of the known ENV receptor, Toll-like receptor 4 (TLR4), on oligodendroglial precursor cells in human brain tissue and in culture. Cultured primary oligodendroglial precursor cells were stimulated with ENV protein to determine the effects of this ligand/receptor interaction.
We demonstrated that the ENV protein is present in close proximity to TLR4-expressing oligodendroglial precursor cells adjacent to multiple sclerosis lesions. Human and rat oligodendroglial precursor cells expressed TLR4, and the ENV-mediated activation of TLR4 led to the induction of proinflammatory cytokines and inducible nitric oxide synthase as well as the formation of nitrotyrosine groups and a subsequent reduction in myelin protein expression.
Our findings suggest that ENV-mediated induction of nitrosative stress via activation of TLR4 results in an overall reduction of the oligodendroglial differentiation capacity, thereby contributing to remyelination failure. Therefore, pharmacological or antibody-mediated inhibition of ENV may prevent the blockade of myelin repair in the diseased or injured central nervous system. Ann Neurol 2013;74:721–732