Restoration of FcRγ/Fyn signaling repairs central nervous system demyelination
Restoration of FcRγ/Fyn signaling repairs central nervous system demyelination
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DOI：
10.1002/jnr.21196
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发表时间：
2007-04-01
影响因子：
4.2
通讯作者：
Asou, Hiroaki
中科院分区：
文献类型：
--
作者：
Seiwa, Chika;Yamamoto, Masahiro;Asou, Hiroaki
髓磷脂破坏会导致严重的神经系统疾病。需要了解控制髓鞘形成和髓鞘再生的机制来制定多发性硬化症 (MS) 等脱髓鞘疾病的治疗策略。我们之前的发现表明免疫球蛋白Fc受体的γ链（FcRγ）和Fyn信号在少突胶质细胞分化和髓鞘形成中至关重要，需要对MS治疗策略进行根本性修改，因为MS患者中的抗原抗体复合物可能诱导髓鞘形成过程的直接失调以及髓鞘的炎症破坏。在这里，我们表明 FcR gamma/Fyn 信号级联在铜宗诱导的脱髓鞘/髓鞘再生中至关重要，但没有淋巴细胞反应。在衰老、铜宗治疗和 FcR gamma/Fyn 基因双敲除诱导的脱髓鞘过程中，磷酸化髓磷脂碱性蛋白 (p-MBP) 的水平，尤其是 21.5-kDa 亚型，但不是总 MBP 的水平显着下降。我们还表明，经过铜宗治疗的老年小鼠在服用草药 Ninjin'yoeito 后可以实现脱髓鞘的恢复，Ninjin'yoeito 是一种针对 FcR gamma/Fyn-Rho-(Rac1)-MAPK (P38 MAPK)-p-MBP 信号级联的有效疗法。这些结果表明FcR7/Fyn信号的恢复代表了治疗脱髓鞘疾病的新方法。 (c) 2007 年 Wiley-Liss, Inc.
Disruption of myelin causes severe neurological diseases. An understanding of the mechanisms that control myelination and remyelination is needed to develop therapeutic strategies for demyelinating diseases such as multiple sclerosis (MS). Our previous finding indicating the critical involvement of the gamma chain of immunogloblin Fc receptors (FcR gamma) and Fyn signaling in oligodendrocyte differentiaion and myelination demands a fundamental revision of the strategies used for MS therapy, because antigen-anti body complexes in MS patients may induce the direct dysregulation of myelination process as well as the inflammatory destruction of myelin sheath. Here we show that the FcR gamma/Fyn signaling cascade is critically involved in cuprizone-induced demyelination/remyelination, with no lymphocytic response. The levels of phosphorylated myelin basic proteins (p-MBPs), especially the 21.5-kDa isoform, but not the levels of total MBPs, decreased markedly during demyelination induced by aging, cuprizone treatment, and double knockout of FcR gamma/Fyn genes. We also showed that the recovery from demyelination in cuprizone-treated and aged mice is achieved after administration of the herbal medicine Ninjin'yoeito, an effective therapy targeting the FcR gamma/Fyn-Rho-(Rac1)-MAPK (P38 MAPK)-p-MBPs signaling cascade. These results suggest that the restoration of FcR7/Fyn signaling represents a new approach for the treatment of demyelinating diseases. (c) 2007 Wiley-Liss, Inc.