Department of Neuroinfection and Neuroimmunology, Beijing Tiantan Hospital, China National Clinical Research Center for Neurological Diseases, Capital Medical University, No.119 South 4thRing West Road, Fengtai District, Beijing 100160, China.
Department of Neurology, Xuanwu Hospital, Capital Medical University, No.45 Changchun Street, Xicheng District, Beijing 100053, China; Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China.
Neuroscience. 2022 Aug 1;496:96-104. doi: 10.1016/j.neuroscience.2022.05.038. Epub 2022 Jun 3.
Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disorder of the central nervous system (CNS) that frequently affects the optic nerve and spinal cord. Interleukin-6 (IL-6) is considered a key cytokine in the pathogenesis of NMOSD, and the level of IL-6 is significantly increased in the sera and cerebrospinal fluid (CSF) of patients with NMOSD. We have reported that the production of IL-6 depends on the JAK/STAT3 signaling pathway. However, it is not clear whether the NF-κB-dependent inflammatory response stimulated by neuromyelitis optica IgG (NMO-IgG) could also drive the production of IL-6 in astrocytes. In this study, we used an in vitro model of primary rat astrocytes stimulated by NMO-IgG to study the role of the NF-κB signaling pathway in mediating the release of IL-6. First, we confirmed that the level of IL-6 was significantly higher in the sera of NMOSD patients than that of healthy people by humoral fluid analysis and that NMO-IgG can significantly induce the release of IL-6 from astrocytes by enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Then, Western blotting and immunocytochemistry showed that NMO-IgG can activate the intracellular NF-κB signaling pathway. Finally, it was found that S3633, an inhibitor of the NF-κB signaling pathway, can effectively inhibit the increase in IL-6 levels. These results prove that the production of IL-6 is partly mediated by the NF-κB signaling pathway, providing a potential effective strategy for targeted treatment of NMOSD.
视神经脊髓炎谱系疾病（NMOSD）是一种中枢神经系统（CNS）的炎症性脱髓鞘疾病，常影响视神经和脊髓。白细胞介素 6（IL-6）被认为是 NMOSD 发病机制中的关键细胞因子，NMOSD 患者的血清和脑脊液（CSF）中 IL-6 水平显著升高。我们已经报道 IL-6 的产生依赖于 JAK/STAT3 信号通路。然而，目前尚不清楚视神经脊髓炎 IgG（NMO-IgG）刺激的 NF-κB 依赖性炎症反应是否也能驱动星形胶质细胞中 IL-6 的产生。在这项研究中，我们使用 NMO-IgG 刺激的原代大鼠星形胶质细胞体外模型来研究 NF-κB 信号通路在介导 IL-6 释放中的作用。首先，我们通过体液分析证实 NMOSD 患者血清中 IL-6 水平明显高于健康人，ELISA 和流式细胞术证实 NMO-IgG 可显著诱导星形胶质细胞释放 IL-6。然后，Western blot 和免疫细胞化学显示 NMO-IgG 可激活细胞内 NF-κB 信号通路。最后发现，NF-κB 信号通路抑制剂 S3633 可有效抑制 IL-6 水平的升高。这些结果证明 IL-6 的产生部分是由 NF-κB 信号通路介导的，为 NMOSD 的靶向治疗提供了一种潜在的有效策略。
