Key Points HuR regulates Th17 cell and Th1-like Th17 cell differentiation. HuR directly and indirectly modulates expression of RUNX1 and RORγt, respectively. Targeting HuR by its inhibitor reduces severity of autoimmune neuroinflammation. Dysregulated Th17 cell differentiation is associated with autoimmune diseases such as multiple sclerosis, which has no curative treatment. Understanding the molecular mechanisms of regulating Th17 cell differentiation will help find a novel therapeutic target for treating Th17 cell–mediated diseases. In this study, we investigated the cell-intrinsic processes by which RNA-binding protein HuR orchestrates Th17 cell fate decisions by posttranscriptionally regulating transcription factors Irf4 and Runx1 and receptor Il12rb1 expression, in turn promoting Th17 cell and Th1-like Th17 cell differentiation in C57BL/6J mice. Knockout of HuR altered the transcriptome of Th17 cells characterized by reducing the levels of RORγt, IRF4, RUNX1, and T-bet, thereby reducing the number of pathogenic IL-17+IFN-γ+CD4+ T cells in the spleen during experimental autoimmune encephalomyelitis. In keeping with the fact that HuR increased the abundance of adhesion molecule VLA-4 on Th17 cells, knockout of HuR impaired splenic Th17 cell migration to the CNS and abolished the disease. Accordingly, targeting HuR by its inhibitor DHTS inhibited splenic Th17 cell differentiation and reduced experimental autoimmune encephalomyelitis severity. In sum, we uncovered the molecular mechanism of HuR regulating Th17 cell functions, underscoring the therapeutic value of HuR for treatment of autoimmune neuroinflammation.

中文翻译：

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RNA 结合蛋白 HuR 促进 Th17 细胞分化并可靶向减少自身免疫性神经炎症

关键点 HuR 调节 Th17 细胞和 Th1 样 Th17 细胞分化。HuR 分别直接和间接调节 RUNX1 和 RORγt 的表达。通过其抑制剂靶向 HuR 可降低自身免疫性神经炎症的严重程度。Th17 细胞分化失调与自身免疫性疾病有关，如多发性硬化症，目前尚无治愈性治疗方法。了解调节 Th17 细胞分化的分子机制将有助于找到治疗 Th17 细胞介导的疾病的新治疗靶点。在这项研究中，我们研究了 RNA 结合蛋白 HuR 通过转录后调节转录因子 Irf4 和 Runx1 以及受体 Il12rb1 表达来协调 Th17 细胞命运决定的细胞内在过程，反过来促进 C57BL/6J 小鼠的 Th17 细胞和 Th1 样 Th17 细胞分化。HuR 的敲除改变了 Th17 细胞的转录组，其特征是降低了 RORγt、IRF4、RUNX1 和 T-bet 的水平，从而减少了实验性自身免疫性脑脊髓炎期间脾脏中致病性 IL-17+IFN-γ+CD4+T 细胞的数量. 与 HuR 增加 Th17 细胞上粘附分子 VLA-4 的丰度这一事实一致，HuR 的敲除会损害脾脏 Th17 细胞向中枢神经系统的迁移并消除该疾病。因此，通过其抑制剂 DHTS 靶向 HuR 可抑制脾脏 Th17 细胞分化并降低实验性自身免疫性脑脊髓炎的严重程度。总之，我们揭示了 HuR 调节 Th17 细胞功能的分子机制，