Regnase-1 and Roquin Nonredundantly Regulate Th1 Differentiation Causing Cardiac Inflammation and Fibrosis
Regnase-1 and Roquin Nonredundantly Regulate Th1 Differentiation Causing Cardiac Inflammation and Fibrosis
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DOI：
10.4049/jimmunol.1701211
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发表时间：
2017-12-15
影响因子：
4.4
通讯作者：
Takeuchi, Osamu
中科院分区：
文献类型：
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作者：
Cui, Xiaotong;Mino, Takashi;Takeuchi, Osamu
Regnase-1 和 Roquin 是 RNA 结合蛋白，对于降解炎症 mRNA 和维持免疫稳态至关重要。尽管这两种蛋白质的缺陷都会导致 T 细胞活化增强，但由于 Regnase-1 和 Roquin 突变时的致死性，它们在 T 细胞中的功能关系尚未阐明。通过使用 Regnase-1 条件等位基因，我们发现 T 细胞中 Regnase-1 和 Roquin 的突变都会导致大量淋巴细胞激活。相比之下，Regnase-1 或 Roquin 的突变对 T 细胞激活的影响程度小于双突变，表明 Regnase-1 和 Roquin 在 T 细胞中非冗余地发挥作用。有趣的是，Regnase-1和Roquin双突变小鼠患有严重炎症和早期纤维化形成，尤其是在心脏中，同时Ifng表达增加，但Il4或Il17a表达增加。一致的是，与单一 Regnase-1 或 Roquin 缺陷的 T 细胞相比，Regnase-1 和 Roquin 的突变会导致脾脏中 Th1 细胞数量大幅增加，但不会导致 Th2 或 Th17 细胞数量大幅增加。 Regnase-1 和 Roquin 能够通过 39 个非翻译区抑制一组参与 Th1 分化的 mRNA 编码因子的表达，例如 Furin 和 Il12rb1。此外，Regnase-1 能够抑制 Roquin mRNA。这种交叉调节可能有助于 T 细胞激活/极化的协同控制。总的来说，我们的结果表明 Regnase-1 和 Roquin 可以维持 T 细胞免疫稳态并协同调节 Th1 极化。
Regnase-1 and Roquin are RNA binding proteins that are essential for degradation of inflammatory mRNAs and maintenance of immune homeostasis. Although deficiency of either of the proteins leads to enhanced T cell activation, their functional relationship in T cells has yet to be clarified because of lethality upon mutation of both Regnase-1 and Roquin. By using a Regnase-1 conditional allele, we show that mutations of both Regnase-1 and Roquin in T cells leads to massive lymphocyte activation. In contrast, mutation of either Regnase-1 or Roquin affected T cell activation to a lesser extent than the double mutation, indicating that Regnase-1 and Roquin function nonredundantly in T cells. Interestingly, Regnase-1 and Roquin double-mutant mice suffered from severe inflammation and early formation of fibrosis, especially in the heart, along with the increased expression of Ifng, but not Il4 or Il17a. Consistently, mutation of both Regnase-1 and Roquin leads to a huge increase in the Th1, but not the Th2 or Th17, population in spleens compared with T cells with a single Regnase-1 or Roquin deficiency. Regnase-1 and Roquin are capable of repressing the expression of a group of mRNAs encoding factors involved in Th1 differentiation, such as Furin and Il12rb1, via their 39 untranslated regions. Moreover, Regnase-1 is capable of repressing Roquin mRNA. This cross-regulation may contribute to the synergistic control of T cell activation/polarization. Collectively, our results demonstrate that Regnase-1 and Roquin maintain T cell immune homeostasis and regulate Th1 polarization synergistically.