Notch1 and its ligand Jagged1 are present in remyelination in a T-cell- and antibody-mediated model of inflammatory demyelination
Notch1 and its ligand Jagged1 are present in remyelination in a T-cell- and antibody-mediated model of inflammatory demyelination
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DOI：
10.1007/s00401-006-0170-9
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发表时间：
2007-02-01
影响因子：
12.7
通讯作者：
Storch, Maria K.
中科院分区：
文献类型：
--
作者：
Seifert, Thomas;Bauer, Jan;Storch, Maria K.
Notch受体及其配体参与中枢神经系统（CNS）发育过程中的髓鞘形成。该通路在成人中枢神经系统中的重新表达已被认为可阻碍多发性硬化症的髓鞘再生。先前的研究也表明，Notch信号的药理抑制可改善实验性自身免疫性脑脊髓炎（EAE）。然而，在最近的一项毒素诱导脱髓鞘的研究中，Notch信号通路的成分在髓鞘再生病变中得到证实，表明髓鞘再生可能在Notch信号的存在下发生。我们检测了notch1免疫反应性（IR）和Jagged1-IR在髓鞘-少突胶质细胞糖蛋白（MOG）诱导的EAE中的表达。在这个模型中，T细胞、抗体和补体级联的联合作用产生了一种密切反映多发性硬化症的病理。Notch1及其配体Jagged1在MOG-EAE病变中有差异表达。巨噬细胞Notch1-IR在活动性脱髓鞘中最高，在再脱髓鞘病变中最低。notch1阳性星形胶质细胞的数量在病变从脱髓鞘到再髓鞘的演变过程中增加。notch1阳性少突胶质细胞只存在于髓鞘再生病变中，而不存在于无髓鞘再生迹象的病变中。星形胶质细胞是脱髓鞘和再生过程中Jagged1-IR的主要来源。总之，我们的研究证明了Notch通路的成分在t细胞和抗体介导的中枢神经系统脱髓鞘动物模型中的脱髓鞘表达。因此，至少在MOG-EAE的范式中，Notch信号不太可能是髓鞘再生失败的原因。
The Notch receptor and its ligands are involved in myelination in central nervous system (CNS) development. Re-expression of this pathway in the adult CNS has been proposed to hamper remyelination in multiple sclerosis. Previous studies also revealed that pharmacological inhibition of Notch signaling ameliorates experimental autoimmune encephalomyelitis (EAE). However, in a recent study in toxin-induced demyelination constituents of the Notch signaling pathway were demonstrated in remyelinating lesions indicating that remyelination may occur in the presence of Notch signaling. We examined the expression of Notch1-immunoreactivity (IR) and Jagged1-IR in EAE induced by myelin-oligodendrocyte glycoprotein (MOG). In this model, the combined action of T cells, antibodies and the complement cascade yields a pathology closely reflecting multiple sclerosis. Notch1 and its ligand Jagged1 were differentially expressed in the lesions of MOG-EAE. Notch1-IR on macrophages was highest in actively demyelinating and lowest in remyelinating lesions. The amount of Notch1-positive astrocytes increased during the lesion evolution from demyelination to remyelination. Notch1-positive oligodendrocytes were exclusively present in remyelinating lesions and not found in lesions without signs of remyelination. Astrocytes represented the major source of Jagged1-IR in demyelination and remyelination. In conclusion, our study proves that constituents of the Notch pathway are expressed in remyelination in an animal model of T-cell- and antibody-mediated CNS demyelination. Thus, it is unlikely, at least in the paradigm of MOG-EAE, that Notch signaling is responsible for a failure of remyelination.