Sema4A is implicated in the acceleration of Th17 cell-mediated neuroinflammation in the effector phase
Sema4A is implicated in the acceleration of Th17 cell-mediated neuroinflammation in the effector phase
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DOI：
10.1186/s12974-020-01757-w
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发表时间：
2020-03-13
影响因子：
9.3
通讯作者：
Okuno, Tatsusada
中科院分区：
文献类型：
--
作者：
Koda, Toru;Namba, Akiko;Okuno, Tatsusada
背景Sema 4A是启动期辅助性T细胞（Th）活化和分化的调节因子，在实验性自身免疫性脑脊髓炎（EAE）和多发性硬化症（MS）的发病机制中发挥重要作用。然而，Sema 4A在效应期的作用仍然难以捉摸。我们的目的是研究Sema 4A在过继转移EAE模型中效应期的作用。临床特征和细胞因子谱的MS患者与高Sema 4A水平进行了详细研究，以澄清与MS患者的Sema 4A水平和疾病活动之间的相关性。方法我们过继转移致脑炎性Th 1或Th 17细胞野生型（WT）或Sema 4A缺陷（Sema 4A KO）小鼠和评估症状的严重程度和中枢神经系统（CNS）内的细胞浸润。此外，我们分析了所有复发缓解型多发性硬化症（RRMS）患者的临床和放射学特征（n = 201），血清IFN-γ和IL-17 A水平（n = 86），IFN-β完全缓解率（n = 38）。结果与WT受体小鼠相比，接受Th 17-偏斜WT髓鞘少突胶质细胞糖蛋白（MOG）特异性致脑炎T细胞的Sema 4A KO受体小鼠的临床评分显着降低。然而，Sema 4A KO受体小鼠在用Th 1偏斜的致脑炎性T细胞转移时显示出与WT受体小鼠相似的疾病活性。骨髓嵌合体研究表明，Sema 4A在造血细胞上表达，而不是在CNS驻留细胞上表达，负责增强Th 17介导的神经炎症。此外，与相当的IFN-γ水平相比，IL-17 A在具有高Sema 4A水平的RRMS患者中显著高于具有低Sema 4A水平的那些患者，具有高Sema 4A水平的患者显示出比具有低Sema 4A水平的那些患者更早的疾病发作、更严重的疾病活动性和IFN-β无反应性。结论Sema 4A不仅参与了Th细胞的启动，还参与了效应期Th 17细胞介导的神经炎症反应的加速，这可能是高血清Sema 4A水平的RRMS患者疾病活动性更高的原因。
Background Sema4A is a regulator of helper T cell (Th) activation and differentiation in the priming phase, which plays an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). However, the role of Sema4A in the effector phase remains elusive. We aimed to investigate the role of Sema4A at the effector phase in adoptively transferred EAE model. Clinical features and cytokine profiles of MS patients with high Sema4A levels were also examined in detail to clarify the correlation between Sema4A levels and disease activity of patients with MS. Methods We adoptively transferred encephalitogenic Th1 or Th17 cells to wild type (WT) or Sema4A-deficient (Sema4A KO) mice and assessed severity of symptoms and cellular infiltration within the central nervous system (CNS). In addition, we analyzed clinical and radiological features (n = 201), levels of serum IFN-gamma and IL-17A (n = 86), complete remission ratio by IFN-beta (n = 38) in all of relapsing-remitting multiple sclerosis (RRMS) patients enrolled in this study. Results Sema4A KO recipient mice receiving Th17-skewed WT myelin oligodendrocyte glycoprotein (MOG)-specific encephalitogenic T cells showed a significant reduction in the clinical score compared to the WT recipient mice. However, Sema4A KO recipient mice showed similar disease activity to the WT recipient mice when transferred with Th1-skewed encephalitogenic T cells. Bone marrow chimeric study indicated that Sema4A expressed on hematopoietic cells, but not the CNS resident cells, are responsible for augmenting Th17-mediated neuroinflammation. Additionally, in contrast to comparable IFN-gamma levels, IL-17A is significantly higher in RRMS patients with high Sema4A level than those with low Sema4A patients with high Sema4A levels showed earlier disease onset, more severe disease activity and IFN-beta unresponsiveness than those with low Sema4A levels. Conclusions Sema4A is involved not only in the Th cell priming but also in the acceleration of Th17 cell-mediated neuroinflammation in the effector phase, which could contribute to the higher disease activity observed in RRMS patients with high serum Sema4A levels.