Human endogenous retrovirus type W envelope protein inhibits oligodendroglial precursor cell differentiation.

Abstract

OBJECTIVE:

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.

METHODS:

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.

RESULTS:

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.

INTERPRETATION:

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.

• Authors: David Kremer, Tanja Schichel, Moritz Förster, Nevena Tzekova, Corinne Bernard, Paul van der Valk, Jack van Horssen, Hans-Peter Hartung, Hervé Perron, Patrick Küry
• Journal: Annals of neurology (Ann Neurol) Vol. 74 Issue 5 Pg. 721-32 (Nov 2013) ISSN: 1531-8249 [Electronic] United States
• PMID: 23836485 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 American Neurological Association.

Chemical References

• Gene Products, env
• Pregnancy Proteins
• Toll-Like Receptor 4
• syncytin

Topics

• Animals
• Cell Differentiation
• Cells, Cultured
• Gene Products, env (genetics, metabolism)
• Humans
• Myelin Sheath (genetics, metabolism)
• Neural Stem Cells (cytology, metabolism)
• Oligodendroglia (cytology, metabolism)
• Pregnancy Proteins (genetics, metabolism)
• Rats
• Toll-Like Receptor 4 (genetics, metabolism)