Hyaluronan blocks oligodendrocyte progenitor maturation and remyelination through TLR2

Abstract

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 lesions. Pathogenderived 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 lowmolecular-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.hyaluronidase | MyD88 | innate immunity I n multiple sclerosis (MS), destruction of CNS myelin accounts for a majority of neurologic symptoms. MS patients typically exhibit a relapsing/remitting course in which relapses result from inflammation and demyelination and remissions result from resolution of inflammation and remyelination. Secondary progressive MS, which typically begins in patients after a decade of relapsing/ remitting MS, exhibits irreversible neurologic disability.Most chronic MS lesions show little if any remyelination. The failure of remyelination in MS theoretically could be the consequence of a deficiency in the number of oligodendrocyte progenitor cells (OPCs), absence of a promyelination signal, or the presence of inhibitory influences on OPCs. It therefore is of interest that the histopathology of the MS lesion has revealed the presence of OPCs and premyelinating oligodendrocytes in chronic MS lesions. The premyelinating oligodendrocytes extend processes that contact but fail to myelinate axons (1-4), thus suggesting failure of remyelination is caused by the loss of promyelination signals or the presence of inhibitory signals.Recently, the glycosaminoglycan hyaluronan was identified within MS lesions and found to inhibit OPC maturation and remyelination in an MS animal model (5). The mechanism underlying this inhibition is unknown. Because hyaluronan can function as an endogenous mammalian ligand for Toll-like receptors (TLRs) 2 and 4 in innate immune cell activation (6-9), we reasoned that TLR stimulation also may be required for hyaluronan-mediated blocking of OPC maturation.Although TLRs and the Drosophila ortholog Toll have welldescribed functions in innate immune cells (6-12), TLRs also have potent functions outside the immune system. Toll and TLR have diverse roles in axonal pathfinding, dorsoventral patterning, and cell-fate determination (13). In particul...

Comment on: PH20 is not expressed in murine CNS and oligodendrocyte precursor cells

“…We2, 4 and others5 also previously reported that the PH20 hyaluronidase is elevated in demyelinating white matter lesions as well as oligodendrocyte progenitor cells. PH20 was also reported to be present, albeit at low levels, in the rat brain in a study on traumatic brain injury 6.…”

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

“…High molecular weight hyaluronan can directly inhibit OPC differentiation in culture. A recent study has found that hyaluronan inhibits OPC differentiation by binding to toll-like receptor 2 (TLR2) in oligodendrocyte lineage cells in culture and that hyaluronidases produced by OPCs convert high molecular weight hyaluronan to the more inhibitory low molecular weight form [46]. Moreover, inhibition of TLR2 and its signaling pathways can block hyaluronan inhibition to enable OPC differentiation.…”

Inhibition of Hyaluronan Synthesis Protects against Central Nervous System (CNS) Autoimmunity and Increases CXCL12 Expression in the Inflamed CNS

“…Several studies suggest that hyaluronan may have proinflammatory roles in the context of CNS autoimmunity: 1) it accumulates in demyelinated CNS lesions in MS and EAE (5,6); 2) HA production by dendritic cells and T-cells promotes antigen presentation and enhances T-cell activation and proliferation (2,3,7,8); 3) HA-CD44 interactions at the CNS vascular endothelium facilitate lymphocyte binding to vessels and CNS infiltration (9 -11); and 4) hyaluronan fragments signal through both Toll-like receptors (TLR) 2 and 4 and thereby stimulate inflammatory gene expression in immune cells (12).…”