The pleotropic cytokine tumor necrosis factor (TNF) is involved in the pathophysiology of multiple sclerosis (MS). In various models of MS, including experimental autoimmune encephalomyelitis (EAE), the membrane-bound form of TNF (tmTNF), which signals primarily via TNFR2, mediates protective and reparative effects, whereas the soluble form (solTNF), which signals primarily via TNFR1, promotes pro-inflammatory and detrimental functions. In this study, we investigated the role of TNFR2 expressed in the oligodendrocyte in the early phase of EAE pathogenesis. We demonstrated that mice with specific ablation of oligodendroglial TNFR2 displayed early onset and higher peak of motor dysfunction when subjected to EAE, in advance of which accelerated infiltration of immune cells was observed as early as 10 days post EAE induction. The immune cell influx was preceded by microglial activation and increased blood brain barrier permeability. Lack of oligodendroglial TNFR2 accelerated the expression of inflammatory cytokines as well as expression and activation of the inflammasome. Gene expression profiling of oligodendrocytes sorted from the spinal cord 14 days post EAE induction showed robust upregulation of inflammatory genes, some of which were elevated in cells lacking TNFR2 compared to controls. Together, our data demonstrate that oligodendrocytes are directly involved in inflammation and immune modulation in CNS disease and this function is regulated, at least in part, by TNFR2.

中文翻译：

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少突胶质细胞通过 TNFR2 信号调节 EAE 中的免疫炎症反应

多效性细胞因子肿瘤坏死因子 (TNF) 参与多发性硬化症 (MS) 的病理生理学。在各种 MS 模型中，包括实验性自身免疫性脑脊髓炎 (EAE)，主要通过 TNFR2 发出信号的膜结合形式的 TNF (tmTNF) 介导保护和修复作用，而主要通过 TNFR1 发出信号的可溶性形式 (solTNF) , 促进促炎和有害功能。在这项研究中，我们研究了 TNFR2 在 EAE 发病早期阶段在少突胶质细胞中表达的作用。我们证明，当经历 EAE 时，具有少突胶质细胞 TNFR2 特异性消融的小鼠表现出早期发作和更高的运动功能障碍峰值，在此之前，早在 EAE 诱导后 10 天就观察到免疫细胞的加速浸润。免疫细胞流入之前是小胶质细胞激活和血脑屏障通透性增加。少突胶质细胞 TNFR2 的缺乏加速了炎性细胞因子的表达以及炎性体的表达和激活。EAE 诱导后 14 天从脊髓中分选的少突胶质细胞的基因表达谱显示炎症基因的强烈上调，与对照相比，其中一些在缺乏 TNFR2 的细胞中升高。总之，我们的数据表明少突胶质细胞直接参与 CNS 疾病的炎症和免疫调节，并且该功能至少部分受 TNFR2 调节。少突胶质细胞 TNFR2 的缺乏加速了炎性细胞因子的表达以及炎性体的表达和激活。EAE 诱导后 14 天从脊髓中分选的少突胶质细胞的基因表达谱显示炎症基因的强烈上调，与对照相比，其中一些在缺乏 TNFR2 的细胞中升高。总之，我们的数据表明少突胶质细胞直接参与 CNS 疾病的炎症和免疫调节，并且该功能至少部分受 TNFR2 调节。少突胶质细胞 TNFR2 的缺乏加速了炎性细胞因子的表达以及炎性体的表达和激活。EAE 诱导后 14 天从脊髓中分选的少突胶质细胞的基因表达谱显示炎症基因的强烈上调，与对照相比，其中一些在缺乏 TNFR2 的细胞中升高。总之，我们的数据表明少突胶质细胞直接参与 CNS 疾病的炎症和免疫调节，并且该功能至少部分受 TNFR2 调节。