Betaine Ameliorates Experimental Autoimmune Encephalomyelitis by Inhibiting Dendritic Cell-Derived IL-6 Production and Th17 Differentiation
Betaine Ameliorates Experimental Autoimmune Encephalomyelitis by Inhibiting Dendritic Cell-Derived IL-6 Production and Th17 Differentiation
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甜菜碱通过抑制树突状细胞衍生的 IL-6 产生和 Th17 分化来改善实验性自身免疫性脑脊髓炎
DOI：
10.4049/jimmunol.1700920
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发表时间：
2018-02-15
影响因子：
4.4
通讯作者：
Du, Changsheng
中科院分区：
文献类型：
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作者：
Yang, Cuixia;Lai, Weiming;Du, Changsheng
分泌IL-17的T细胞（Th17细胞）在包括多发性硬化症（MS）在内的多种自身免疫性疾病中发挥致病作用，而树突状细胞（DC）衍生的细胞因子在促进初始CD4（+）T细胞分化为Th细胞亚群（Th1和Th17）方面发挥着关键作用。因此，阻断 DC 产生的关键细胞因子的小分子对于治疗多发性硬化症将是有益的。在本文中，我们报道甜菜碱治疗通过抑制 DC 衍生的 IL-6 产生和 Th17 分化来改善 MS 发病机制。使用实验性自身免疫性脑脊髓炎（一种广泛使用的多发性硬化症小鼠模型），我们发现，与媒介物治疗组相比，甜菜碱治疗的小鼠表现出较轻的实验性自身免疫性脑脊髓炎症状，包括较低的临床评分、白细胞浸润减少和中枢神经系统广泛脱髓鞘程度较轻。此外，在外周免疫系统和中枢神经系统中观察到 Th17 细胞（MS 进展的主要致病效应细胞之一）的百分比显着降低。有趣的是，在体外 Th17 分化测定中，在媒介物和甜菜碱处理组之间没有观察到 Th17 细胞的显着变化，而在体外 DC 培养实验中，甜菜碱处理显着降低了 DC 衍生的 IL-6 产量。在 DC-T 细胞共培养实验中，甜菜碱处理后观察到 Th17 分化显着降低。所有这些数据都表明甜菜碱通过减少 DC 产生 IL-6 来间接抑制 Th17 分化。简而言之，我们的研究结果证明了甜菜碱在调节多发性硬化症发病机制中的关键作用，并表明它可以作为治疗多发性硬化症的潜在新候选药物。
IL-17-secreting T cells (Th17 cells) play a pathogenic role in multiple autoimmune diseases, including multiple sclerosis (MS), and dendritic cell (DC)-derived cytokines play pivotal roles in promoting the differentiation of naive CD4(+) T cells into Th cell subsets (Th1 and Th17). Therefore, small molecules blocking the key cytokines produced by DCs will be beneficial in MS. In this article, we report that betaine treatment ameliorates MS pathogenesis by inhibiting DC-derived IL-6 production and Th17 differentiation. Using experimental autoimmune encephalomyelitis, a widely used mouse model of MS, we found that, compared with the vehicle-treated group, betaine-treated mice exhibited less severe experimental autoimmune encephalomyelitis symptoms, including lower clinical scores, reduced leukocyte infiltration, and less extensive demyelination in the CNS. Moreover, a significantly lower percentage of Th17 cells, one of the major pathogenic effector cells in MS progression, was observed in the peripheral immune system and in the CNS. Interestingly, in the in vitro Th17-differentiation assay, no significant change in Th17 cells was observed between the vehicle-and betaine-treated groups, whereas in the in vitro DC culture experiment, betaine treatment significantly decreased DC-derived IL-6 production. In the DC-T cell coculture experiment, a significantly decreased Th17 differentiation was observed upon betaine treatment. All of these data demonstrated that betaine inhibited Th17 differentiation indirectly by reducing IL-6 production by DCs. In brief, our findings demonstrated the pivotal roles of betaine in modulating MS pathogenesis and suggested that it may serve as a potential novel drug candidate for the treatment of MS.