Circular RNA circSnx5 Controls Immunogenicity of Dendritic Cells through the miR-544/SOCS1 Axis and PU.1 Activity Regulation
Circular RNA circSnx5 Controls Immunogenicity of Dendritic Cells through the miR-544/SOCS1 Axis and PU.1 Activity Regulation
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环状 RNA circSnx5 通过 miR-544/SOCS1 轴和 PU.1 活性调节控制树突状细胞的免疫原性
DOI：
10.1016/j.ymthe.2020.07.001
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发表时间：
2020-11-04
影响因子：
12.4
通讯作者：
Yu, Bo
中科院分区：
文献类型：
--
作者：
Chen, Qi;Mang, Ge;Yu, Bo
树突状细胞(DC)可以协调免疫或耐受反应，传递有关功能状态的信息。新出现的研究表明，环状RNA(CircRNAs)参与免疫；然而，它们是否在转录水平上调控DC的发育和功能仍不清楚。在这项研究中，我们确定了一种新的CircRNA，CircSnx5，在调节DC驱动的免疫和耐受方面发挥了核心作用。异位CircSnx5抑制DC的活化，促进DC的耐受功能的发展，而CircSnx5基因敲除则促进DC的活化和炎症表型。从机制上讲，CircSnx5可以作为miR-544海绵，减弱miRNA对细胞因子信号转导抑制因子1(SOCS1)的靶向抑制作用，抑制PU1的核转位，调节DC的激活和功能。此外，在DC中发现了主要的剪接因子，其中异质性核核糖核蛋白(HnRNP)C是CircSnx5产生所必需的。此外，我们的数据表明，免疫CircSnx5条件树突状细胞延长了小鼠同种异体心脏移植的存活时间，并减轻了实验性自身免疫性心肌炎。综上所述，我们的结果揭示了CircSnx5是微调DC功能的关键调节器，表明CircSnx5可能成为免疫相关疾病的潜在治疗途径。
Dendritic cells (DCs) can orchestrate either immunogenic or tolerogenic responses to relay information on the functional state. Emerging studies indicate that circular RNAs (circRNAs) are involved in immunity; however, it remains unclear whether they govern DC development and function at the transcriptional level. In this study, we identified a central role for a novel circRNA, circSnx5, in modulating DC-driven immunity and tolerance. Ectopic circSnx5 suppresses DC activation and promotes the development of tolerogenic functions of DCs, while circSnx5 knockdown promotes their activation and inflammatory phenotype. Mechanistically, circSnx5 can act as a miR-544 sponge to attenuate miRNA-mediated target depression on suppressor of cytokine signaling 1 (SOCS1) and inhibit nuclear translocation of PU.1, regulating DC activation and function. Furthermore, the main splicing factors (SFs) were identified in DCs, of which heterogeneous nuclear ribonucleoprotein (hnRNP) C was essential for circSnx5 generation. Moreover, our data demonstrated that vaccination with circSnx5-conditioned DCs prolonged cardiac allograft survival in mice and alleviated experimental autoimmune myocarditis. Taken together, our results revealed circSnx5 as a key modulator to fine-tune DC function, suggesting that circSnx5 may serve as a potential therapeutic avenue for immune-related diseases.