The effects of NF-kB on oligodendrocytes in models of multiple sclerosis

项目摘要/摘要： 多发性硬化症(MS)是中枢神经系统的一种慢性炎症性脱髓鞘疾病。人们普遍认为 多发性硬化症及其动物模型实验性自身免疫性脑脊髓炎(EAE)是由一种自身免疫启动的 对少突胶质细胞和髓鞘的反应。有证据表明，少突胶质细胞死亡是由 炎性攻击在MS和EAE的发生发展中起重要作用。核因子κB(NF-κB) 通过调节炎症和细胞，在炎症性疾病中发挥关键作用，包括MS和EAE 生存能力。虽然在MS和EAE的少突胶质细胞中观察到了NF-κB的激活，但 核因子-κB在这些疾病中对少突胶质细胞的作用在很大程度上尚不清楚。我们实验室和其他机构的体外研究 多组研究表明，在炎症介质的作用下，NF-κB的激活促进了少突胶质细胞的存活。 我们最近的研究表明，胰腺内质网激酶(PERK)信号的激活在 少突胶质细胞对EAE小鼠的保护作用以及PERK信号转导通路对EAE的保护作用 EAE时少突胶质细胞与NF-κB的激活有关。重要的是，我们的初步数据显示 少突胶质细胞特异性的NF-κB失活加剧了干扰素-γ诱导的髓鞘形成 幼年发育期小鼠少突胶质细胞死亡和髓鞘过少。我们的初步观察也 提示NF-κB在少突胶质细胞中的特异性失活显著增加了疾病的严重程度。 因此，我们假设，NF-κB的激活是细胞自主作用的，以保护少突胶质细胞免受 炎性发作在MS和EAE中的作用及激活PERK的保护作用 这些疾病中的少突胶质细胞。在第一个具体目标中，我们将确定NF-κB失活是否起作用 以细胞自主的方式使(重新)髓鞘形成的少突胶质细胞易受有害影响 干扰素-γ是MS和EAE中的关键促炎细胞因子。在第二个具体目标中，我们将确定是否 NF-κB激活细胞-自主保护少突胶质细胞免受炎症攻击，导致 减轻EAE疾病的严重程度。在第三个具体目标中，我们将确定NF-κB的激活是否 在EAE过程中，PERK信号对少突胶质细胞的保护作用所必需的。这项工作将定义 NF-κB途径，尤其是PERK-NF-κB途径对少突胶质细胞(两者)的细胞保护作用 MS和EAE中的成熟和重新髓鞘少突胶质细胞)，这将促进我们对 MS中少突胶质细胞活性的调控机制

Project Summary/Abstract: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease in the CNS. It is generally believed that MS and its animal model, experimental autoimmune encephalomyelitis (EAE), are initiated by an autoimmune reaction against oligodendrocytes and myelin. Evidence suggests that oligodendrocyte death induced by inflammatory attacks contributes significantly to the development of MS and EAE. Nuclear Factor κ B (NF-κB) plays a critical role in inflammatory diseases, including MS and EAE, by regulating inflammation and cell viability. Although activation of NF-κB has been observed in oligodendrocytes in MS and EAE, the effects of NF-κB on oligodendrocytes in these diseases remain largely unexplored. In vitro studies from our lab and other groups show that NF-κB activation promotes oligodendrocyte survival in response to inflammatory mediators. Our recent study shows that activation of pancreatic endoplasmic reticulum kinase (PERK) signaling in oligodendrocytes protects mice against EAE and that the protective effects of PERK signaling on oligodendrocytes during EAE are associated with NF-κB activation. Importantly, our preliminary data showed that NF-κB inactivation specifically in oligodendrocytes exacerbated interferon-γ (IFN-γ)-induced myelinating oligodendrocyte death and hypomyelination in young, developing mice. Our preliminary observation also suggested that NF-κB inactivation specifically in oligodendrocytes significantly increased EAE disease severity. Therefore, we hypothesize that NF-κB activation acts cell-autonomously to protect oligodendrocytes against inflammatory attacks in MS and EAE and accounts for the protective effects of PERK activation on oligodendrocytes in these diseases. In the first specific aim, we will determine whether NF-κB inactivation acts in a cell-autonomous manner to render (re)myelinating oligodendrocytes vulnerable to the detrimental effects of IFN-γ, a key proinflammatory cytokine in MS and EAE. In the second specific aim, we will determine whether NF-κB activation cell-autonomously protects oligodendrocytes against inflammatory attacks, resulting in attenuation of EAE disease severity. In the third specific aim, we will determine whether NF-κB activation is required for the protective effects of PERK signaling on oligodendrocytes during EAE. This work will define the cytoprotective effects of the NF-κB pathway, particularly the PERK-NF-κB pathway, on oligodendrocytes (both mature and remyelinating oligodendrocytes) in MS and EAE, which will advance our understanding of the mechanisms governing oligodendrocyte viability in MS.