Chlorzoxazone Alleviates Experimental Autoimmune Encephalomyelitis via Inhibiting IL-6 Secretion of Dendritic Cells
Chlorzoxazone Alleviates Experimental Autoimmune Encephalomyelitis via Inhibiting IL-6 Secretion of Dendritic Cells
复制标题
氯唑沙宗通过抑制树突状细胞分泌 IL-6 减轻实验性自身免疫性脑脊髓炎
DOI：
10.4049/jimmunol.2100169
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Changsheng Du
中科院分区：
文献类型：
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作者：
Jie Lv;Mengyao Han;Zhenglong Xiang;Ran Gong;Changjie Shi;Qiuhong Hua;Ru Zhang;Changsheng Du
多发性硬化症（MS）是一种慢性炎症性脱髓鞘自身免疫性疾病，伴有中枢神经系统慢性炎症性脱髓鞘。实验性自身免疫性脑脊髓炎（EAE）是研究MS的重要动物模型，有许多与MS相似的病理现象。 Th17 细胞是 EAE 和 MS 发病机制的重要调节因子。 Th 细胞发育所需的大多数细胞因子由 APC 分泌，例如树突状细胞 (DC)。因此，可以通过抑制 DC 分泌细胞因子来改善 MS。在这项研究中，我们报道了氯唑沙宗可以通过抑制 DC 产生 IL-6 来改善 EAE 发病机制。氯唑沙宗治疗组小鼠的EAE症状得到缓解，主要表现为临床评分降低、免疫细胞数量减少、中枢神经系统脱髓鞘减少。而且，脾脏和中枢神经系统中Th17细胞的比例显着下降。体外实验表明，氯唑沙宗处理显着减少了 DC 衍生的 IL-6 的产生。在 DC-T 细胞共培养实验中，氯唑沙宗处理后观察到 Th17 分化显着降低。此外，还进行了质谱分析以阐明氯唑沙宗影响 EAE 和 DC 功能的机制。我们发现氯唑沙宗抑制 DC 分泌 IL-6 的作用可能是通过 AMP 激活的蛋白激酶途径介导的。总的来说，我们的研究阐明了氯唑沙宗在调节 EAE 发病机制中的关键作用，并表明它可以作为 MS 患者的新药。要点 氯唑沙宗减少 EAE 小鼠脾脏和 CNS 中 Th17 的分化。氯唑沙宗以剂量依赖性方式抑制 DC 产生 IL-6。氯唑沙宗通过 AMPK 途径影响 DC 的功能。
Multiple sclerosis (MS) is a chronic inflammatory demyelinating autoimmune disease with chronic inflammatory demyelination of the CNS. Experimental autoimmune encephalomyelitis (EAE) is an important animal model to study MS, with many pathological phenomena similar to MS. Th17 cells are important regulators of EAE and MS pathogenesis. Most cytokines needed for Th cell development are secreted by APCs, such as dendritic cells (DCs). Consequently, MS could be improved by inhibiting cytokine secretion from DCs. In this study, we reported that chlorzoxazone could ameliorate EAE pathogenesis via inhibiting IL-6 production by DCs. The EAE signs in the chlorzoxazone-treated group of mice were relieved, which was mainly manifested as lower clinical scores, a decrease in the number of immune cells, and a reduction of demyelination in the CNS. Moreover, the proportion of Th17 cells in the spleen and CNS decreased significantly. In vitro experiments showed that chlorzoxazone treatment significantly reduced DC-derived IL-6 production. In the DC–T cell coculture experiment, significantly decreased Th17 differentiation was observed after chlorzoxazone treatment. In addition, mass spectrometric analysis was performed to elucidate the mechanism by which chlorzoxazone affected EAE and DC function. We showed that the effect of chlorzoxazone on inhibiting the secretion of IL-6 by DCs may be mediated via the AMP-activated protein kinase pathway. Overall, our study elucidated the key role of chlorzoxazone in regulating EAE pathogenesis and suggested that it might be used as a new drug for MS patients. Key Points Chlorzoxazone reduced Th17 differentiation in the spleen and CNS in EAE mice. Chlorzoxazone inhibited IL-6 production by DCs in a dose-dependent manner. Chlorzoxazone affected the function of DCs through the AMPK pathway.