Selective inhibition of TLR2 stimulates the maturation of oligodendroglial progenitor cells to oligodendrocytes.

It is important to describe new technologies for overcoming the barrier and promoting remyelination because many axons remain demyelinated in the CNS of multiple sclerosis (MS) patients. Recent studies indicate that LR2 is a negative regulator of maturation of oligodendroglial progenitor cells (OPCs) to oligodendrocytes (OLs) and that TLR2 is present in human MS chronic lesions. However, until recently, there was no specific inhibitor of TLR2. Therefore, we have engineered a peptide corresponding to the TLR2-interacting domain of MyD88 (TIDM) that specifically inhibits TLR2, but not other TLRs. This study underscores the importance of wild type TIDM (wtTIDM) peptide in promoting the maturation of OPCs to oligodendrocytes. The expression of different maturation markers including PLP, MBP and MOG increased in cultured OPCs in response to wtTIDM, but not mTIDM. While investigating mechanisms, we found that wtTIDM peptide increased the maturation of OPCs isolated from TLR4-/- mice, but not TLR2-/- mice, indicating that wtTIDM requires the association with TLR2, but not TLR4, to exhibit this new function. Finally, as evident from double label immunohisto-chemistry and Western blotting, intranasal administration of wtTIDM, but not mTIDM, was capable of increasing OPC maturation and promoting remyelination in the corpus callosum of cuprizone-intoxicated mouse model of demyelination. These results indicate that wtTIDM stimulates the maturation of OPCs via TLR2 and that intranasal wtTIDM may be further evaluated preclinically for stimulating remyelination.