Hyaluronan blocks oligodendrocyte progenitor maturation and remyelination through TLR2
Hyaluronan blocks oligodendrocyte progenitor maturation and remyelination through TLR2
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DOI：
10.1073/pnas.1006496107
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发表时间：
2010-06-22
影响因子：
11.1
通讯作者：
Vartanian, T.
中科院分区：
文献类型：
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作者：
Sloane, J. A.;Batt, C.;Vartanian, T.
髓鞘再生的失败是多发性硬化症（MS）持续神经症状的主要原因。MS病变含有透明质酸沉积物，可抑制少突胶质细胞前体细胞（OPC）成熟。然而，这种抑制背后的机制尚不清楚。我们在这里报告，Toll样受体2（TLR 2）表达的少突胶质细胞，并在MS病变上调。病原体衍生的TLR 2激动剂，但不是其他TLR的激动剂，在体外抑制OPC成熟。海洛葡聚糖介导的OPC成熟抑制需要TLR 2和MyD 88，一种TLR 2衔接分子。TLR 2的消融表达也增强溶血素动物模型中的髓鞘再生。由OPCs表达的透明质酸酶将透明质酸降解为透明质酸寡聚体，这是透明质酸/TLR 2信号传导的需要。MS病变包含TLR 2（+）少突胶质细胞和低分子量透明质酸，这与它们对MS髓鞘再生的重要性一致。因此，我们已经确定了控制MS髓鞘再生失败的机制，其中透明质酸被透明质酸酶降解为透明质酸低聚物，其通过TLR 2-MyD 88信号传导阻断OPC成熟和髓鞘再生。
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. 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.