Hyaluronan blocks oligodendrocyte progenitor maturation and remyelination through TLR2

Failure of remyelination is largely responsible for sustained neurologic symptoms in multiple sclerosis (MS). MS lesions contain hyaluronan deposits that inhibit oligodendrocyte precursor cell (OPC) maturation. However, the mechanism behind this inhibition is unclear. We report here that Toll-like r...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2010-06, Vol.107 (25), p.11555-11560
Main Authors: Sloane, J. A., Batt, C., Ma, Y., Harris, Z. M., Trapp, B., Vartanian, T., Sidman, Richard L.
Format: Article
Language:English
Subjects:
Adult
Animals
Antibodies
Biological Sciences
Case-Control Studies
Cell Lineage
Cell lines
Cells
Cultured cells
Enzymes
Female
Gene expression
Humans
Hyaluronic Acid - metabolism
Hyaluronoglucosaminidase - metabolism
Lesions
Lysophosphatidylcholines
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Middle Aged
Molecular weight
Molecules
Multiple sclerosis
Multiple Sclerosis - metabolism
Myelin Sheath - metabolism
Myeloid Differentiation Factor 88 - metabolism
Neuroglia
Neuroglia - metabolism
Oligodendroglia
Oligodendroglia - cytology
Progenitor cells
Rats
Rats, Sprague-Dawley
Signal Transduction
Stem Cells - cytology
T cell receptors
Toll like receptors
Toll-Like Receptor 2 - metabolism
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Summary:Failure of remyelination is largely responsible for sustained neurologic symptoms in multiple sclerosis (MS). MS lesions contain hyaluronan deposits that inhibit oligodendrocyte precursor cell (OPC) maturation. However, the mechanism behind this inhibition is unclear. We report here that Toll-like receptor 2 (TLR2) is expressed by oligodendrocytes and is up-regulated in MS lesion. Pathogen-derived TLR2 agonists, but not agonists for other TLRs, inhibit OPC maturation in vitro. Hyaluronan-mediated inhibition of OPC maturation requires TLR2 and MyD88, a TLR2 adaptor molecule. Ablated expression of TLR2 also enhances remyelination in a lysolecithin animal model. Hyaluronidases expressed by OPCs degrade hyaluronan to hyaluronan oligomers, a requirement for hyaluronan/TLR2 signaling. MS lesions contain both TLR2⁺ oligodendrocytes and low-molecular-weight hyaluronan, consistent with their importance to remyelination in MS. We thus have defined a mechanism controlling remyelination failure in MS where hyaluronan is degraded by hyaluronidases into hyaluronan oligomers that block OPC maturation and remyelination through TLR2-MyD88 signaling.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1006496107