THE INTEGRATION OF IL-17 AND NOTCH SIGNALING IN THE PATHOGENESIS OF CNS INFLAMMATION

项目摘要 多发性硬化症(MS)是一种中枢神经系统(CNS)炎症性脱髓鞘疾病。 越来越多的证据表明，抑制再髓鞘形成是永久性的主要原因。 神经退行性变。然而，抑制OPC分化和再髓鞘形成的确切机制 仍然是一个活跃的研究领域。而炎症相关的NOTCH1激活与 多发性硬化症的髓鞘再生缺陷--炎症过程中NOTCH1参与的确切机制 回应仍然难以捉摸。利用多发性硬化症的动物模型实验性自身免疫性脑脊髓炎(EAE)， 我们和其他人已经证实，IL-17信号对中枢神经系统炎症的诱导至关重要。我们 现已发现IL-17和NOTCH1信号的直接整合在损伤中起主导作用 OPC的分化。IL-17刺激诱导NOTCH1胞内结构域(NICD1)的释放 在与星形胶质细胞共培养的OPC中。IL-17R通过细胞外途径与NOTCH1相互作用 结构域，这有助于NICD1的切割。随后，IL-17信号转导的适配蛋白Act1， 与NICD1形成复合体，然后Act1-NICD1复合体移位到细胞核内。Act1-NICD1 复合体促进含RBP-J的转录复合体在NOTCH1启动子上的组装 涉及中枢神经系统炎症的靶基因。此外，一个干扰IL-17RA-NOTCH1的诱骗多肽 相互作用抑制IL-17诱导的NICD裂解，减少IL-17诱导的OPC增殖并减弱 EAE模型髓鞘丢失情况。根据这些发现，我们假设IL-17-NOTCH1途径驱动了 表达一组特定的基因以促进炎症和抑制OPC分化，从而 损害脱髓鞘疾病的重新髓鞘形成过程。我们将通过目标1验证这一假设： 探讨IL-17-NOTCH1整合抑制OPC分化的分子机制。 目的：研究IL-17-NOTCH1整合对髓鞘再生过程的影响。完成 这一建议将为IL-17和IL-17信号通路的关键整合提供根本性的见解 NOTCH1，它是脱髓鞘疾病发病机制的基础，为 通过促进多发性硬化患者的髓鞘再生。

Project Summary Multiple Sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). Increasing evidence indicates that the inhibition of remyelination is a major cause of the permanent neurodegeneration. However the precise mechanism that inhibits OPCs differentiation and remyelination remains an active area of research. While inflammation-associated NOTCH1 activation was implicated in defective remyelination in MS, the precise mechanism by which NOTCH1 was engaged during inflammatory response remains elusive. Using experimental autoimmune encephalomyelitis (EAE), an animal model of MS, we and others have established that IL-17 signaling is crucial for the induction of inflammation in the CNS. We have now discovered a direct integration of IL-17 and NOTCH1 signaling that plays a dominant role in impairing the differentiation of OPCs. IL-17 stimulation induced the release of the intracellular domain of NOTCH1 (NICD1) in the OPCs co-cultured with astrocytes. Mechanistically, IL-17R interacts with NOTCH1 via the extracellular domain, which facilitates the cleavage of NICD1. Subsequently, Act1, the adaptor protein for IL-17 signaling, forms a complex with NICD1, followed by translocation of Act1-NICD1 complex into the nucleus. Act1-NICD1 complex promotes the assembly of RBP-J containing transcriptional complex on the promoters of NOTCH1 target genes implicated in CNS inflammation. Furthermore, a decoy peptide disrupting the IL-17RA–NOTCH1 interaction inhibited IL-17-induced NICD cleavage, reduced IL-17-induced OPC prolifereation and attenuated the myelin loss in EAE model. Based on these findings, we hypothesize IL-17-NOTCH1 pathway drives the expression of a specific set of genes to promote inflammation and inhibition of OPC differentiation, thereby impairing the remyelination process in the demyelinating disease. We will test this hypothesis through Aim 1: Investigate the molecular mechanism of the inhibitory role of IL-17-NOTCH1 integration on OPC differentiation. Aim 2: Investigate the in vivo impact of IL-17-NOTCH1 integration on remyelination process. The completion of this proposal will provide fundamental insight into the critical integration of signaling pathways of IL-17 and NOTCH1, which underlies the pathogenesis of demyelinating disease, offering novel therapeutic strategies for MS patients by promoting remyelination.