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

项目概要/摘要： 多发性硬化（MS）是中枢神经系统的慢性炎性脱髓鞘疾病。一般认为 MS及其动物模型，实验性自身免疫性脑脊髓炎（EAE），是由自身免疫性 对少突胶质细胞和髓磷脂的反应。有证据表明， 炎性发作显著促进MS和EAE的发展。核因子κ B（NF-κB） 在炎症性疾病中起关键作用，包括MS和EAE，通过调节炎症和细胞增殖， 生存能力虽然在MS和EAE的少突胶质细胞中观察到NF-κB的活化，但 在这些疾病中，少突胶质细胞上的NF-κB在很大程度上尚未探索。我们实验室的体外研究和其他 组显示NF-κB活化促进了响应炎症介质的少突胶质细胞存活。 我们最近的研究表明，胰腺内质网激酶（PERK）信号的激活， 少突胶质细胞保护小鼠免受EAE，PERK信号转导对EAE的保护作用。 EAE时少突胶质细胞与NF-κB活化有关。重要的是，我们的初步数据显示， 少突胶质细胞NF-κB的失活加重了IFN-γ诱导的髓鞘形成 少突胶质细胞死亡和髓鞘形成不足。我们的初步观察还表明， 提示NF-κB失活特异性地在少突胶质细胞中显著增加EAE疾病的严重程度。 因此，我们假设NF-κB活化是细胞自主的，以保护少突胶质细胞免受 在MS和EAE的炎症攻击，并解释了PERK激活的保护作用， 少突胶质细胞在这些疾病中的作用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）髓鞘化少突胶质细胞易受有害影响 IFN-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 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活化是否是 EAE期间PERK信号对少突胶质细胞的保护作用所需的。这项工作将定义 NF-κB通路，特别是PERK-NF-κB通路对少突胶质细胞的细胞保护作用（两者均 成熟和髓鞘再生少突胶质细胞）在MS和EAE，这将促进我们的理解， 多发性硬化症中少突胶质细胞活力的控制机制。

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.