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通讯作者:

钱粉红,E-mail:zhaoqian604@126.com

中图分类号:R562.2

文献标识码:A

文章编号:1007-4368(2022)04-595-05

DOI:10.7655/NYDXBNS20220422

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目录contents

    摘要

    环状RNA(circular RNA,circRNA)是一类特殊的非编码RNA,参与许多细胞过程,与多种疾病的发生发展相关。 circRNA在先天免疫、炎症反应中发挥重要作用,已有研究表明circRNA与慢性炎症性疾病关系密切。哮喘是一种慢性气道炎症,其发病机制尚不明确。本文就circRNA与哮喘的关系进行综述。

    Abstract

    CircRNAs are one class of especial non⁃coding RNAs which are associated with numerous cellular process and involved in the development of many diseases. Recent studies indicate that circRNAs play important roles in innate immunity and are related to chronic inflammatory disease. Asthma is a chronic airway inflammation and its pathogenesis is unclear. This review summarizes the relationship between circRNAs and asthma.

    关键词

    哮喘环状RNA先天免疫微小RNA

  • 环状RNA(circular RNA,circRNA)是一类新近发现有重要作用的共价闭合环状非编码RNA。最初被认为是转录过程中异常剪接的副产品。2013年发表在《自然》杂志上的一篇文章提出,circRNA可以充当微小RNA(microRNA,miRNA)海绵发挥重要的作用,从此circRNA成为非编码RNA领域的研究热点[1]。circRNA参与许多疾病的发生发展过程,在肿瘤领域的研究相对集中[2]。支气管哮喘简称哮喘,是由多种细胞及其组分参与的慢性气道炎症,目前其发病机制尚不明确。相关研究指出circRNA在先天免疫、炎症反应中发挥重要的作用[3-4]。本文结合circRNA领域最新研究成果,就其与哮喘的密切关系作一综述。

  • 1 circRNA概述

  • 1.1 circRNA的主要特点和分类

  • circRNA是一类特殊的非编码RNA分子,与传统的线性RNA(含5′帽结构及3′多聚腺苷酸尾结构)不同,circRNA将5′和3′末端共价连接呈封闭环状结构,使其不易被核苷酸外切酶降解,在细胞中稳定存在,表达丰富,具有进化的保守性及组织特异性[5-8]。circRNA主要有以下4种亚型:外显子circRNA(ecircRNA)、内含子circRNA(ciRNA)、外显子⁃内含子circRNA(EIciRNA)以及其他非经典的circRNA,如tRNA内含子circRNA(tricRNA)、病毒circRNA等。

  • 1.2 circRNA的生物学功能

  • circRNA的细胞定位在一定程度上决定其行使的功能。ciRNA、EIciRNA主要位于细胞核内,能与RNA聚合酶等相互作用,在转录水平上调节基因的表达[9]。主要分布于细胞质的ecircRNA,其可能来自细胞核向细胞质的定向运输,也可能来源于核膜破裂时的主动逃逸,通过竞争性结合miRNA,在转录后水平调控靶基因表达。circRNA通过与RNA结合蛋白结合,在一定程度上影响线性RNA的生成和功能,也可通过充当蛋白间的支架,调节蛋白的修饰和降解,调节下游细胞信号转导通路[10-11]。同时,蛋白质因子能够诱导特定circRNA的环化,发挥稳定剪接序列和抑制典型的线性剪接的双重作用[2]。此外,circRNA虽为非编码RNA,但部分circRNA也能够被翻译成短肽[12]。人类circRNA中N6 ⁃甲基腺苷(N6 ⁃methyladenosine,m6 A)修饰可以驱动翻译,且有数百个内源性circRNA具有翻译潜能[13]。目前越来越多证据表明circRNA参与哮喘发病的表观遗传学机制,从而影响哮喘的一系列病理生理过程。

  • 2 circRNA与哮喘的相关性研究

  • 2.1 circRNA与先天免疫

  • 先天免疫细胞如先天性淋巴样细胞(ILC)和树突状细胞(DC)在受到致敏原刺激后募集到肺部,引起肺部炎症以及免疫异常是化学性哮喘的发病机制之一。circSnx5能减轻miR⁃544介导的负向调控SOCS1及PU.1的核转运作用,调控DC的激活以及免疫原性[14]。巨噬细胞能够通过释放炎性介质以及与其他细胞相互作用来参与气道炎症。有研究报道[15-16],circRNA可能参与巨噬细胞的活化及免疫应答。关于circRNA调控先天免疫目前有以下两种机制。双链RNA依赖的蛋白质激酶(double⁃ stranded RNA⁃dependent protein kinase,PKR)是细胞经干扰素诱导产生的一种蛋白激酶,有较为保守的双链RNA结合结构域,在双链RNA的激活下可阻止蛋白质合成,抑制病毒的复制和肿瘤细胞的生长。而76%的circRNA能够在细胞中形成16~26bp的双链RNA。这种较短的双链RNA与PKR结合后,可以阻断PKR的激活,从而抑制先天免疫反应[3]。Chen等[17] 提出,外源性circRNA可以充当抗原诱导体内抗原特异性T细胞活化、抗体产生和抗肿瘤免疫。m6 A修饰可以降低外源性circRNA的免疫原性,从而抑制先天免疫。先天免疫的损伤与干扰素的释放以及抗病毒反应有关。研究发现1型、3型干扰素的缺失与下呼吸道病毒感染是儿童哮喘发生发展的重要危险因素[18]。哮喘是一种慢性气道炎症性疾病,辅助性T细胞亚群功能紊乱是哮喘免疫异常的重要机制,这种病原体与宿主的相互作用可能激活适应性免疫反应导致Th1/Th2失衡以及Treg/Th17失衡,从而参与哮喘的发生发展[19]。上述两种circRNA对先天免疫的调控机制提示了circRNA可能在机体对外界刺激做出先天免疫应答中具有重要的作用。那么从circRNA水平出发,通过调控circRNA表达以及表观遗传修饰可能提高机体先天免疫的能力,从而规避哮喘发生的风险,预防哮喘的发生发展。

  • 2.2 circRNA与环境因素

  • 哮喘的发病是遗传因素和环境因素共同作用的结果。环境因素的刺激可导致表观遗传学的改变,从而影响某些基因的激活[20]。在与空气直接接触的气道上皮中存在许多哮喘易感基因,其中支气管上皮在哮喘的发生发展过程中发挥重要作用, Th2细胞及其细胞因子可以降低哮喘患者支气管上皮细胞连接的完整性[21],使上皮细胞的屏障功能被破坏,在受到过敏原、空气污染物以及病原微生物等刺激时,支气管上皮细胞产生炎症反应和异常的修复反应是哮喘气道高反应性和气道重塑的重要机制[22]。研究表明空气中PM2.5浓度升高,可加重哮喘患者喘息和呼吸困难的症状,但其具体的机制尚不明确[23]。Jia等[24] 研究发现circRNA406961在PM2.5介导的支气管上皮炎症反应中可能与白介素增强子结合因子相互作用,通过激活STST3/JNK通路下调炎症因子白介素(interleukin,IL)⁃6及IL⁃8的表达来发挥抑制炎症的作用。薛海南等[25] 研究发现稀土氧化钕染毒组的人支气管上皮细胞(human bronchial epithelial cell,16HBE)分泌的炎症因子较对照组明显增高,对80 μg/mL处理组的细胞微阵列RNA测序结果显示有1 263种circRNA差异性表达。选取5个上调和5个下调的circRNA用实时荧光定量PCR验证结果与芯片的趋势一致。其中下调趋势最明显的hsa_circRNA_0080083与氧化钕的浓度呈线性负相关。 Hua等[26]研究了circRNA 0039411在稀土氧化钕介导的16HBE炎症反应和功能障碍中的作用和机制。circRNA 0039411可以充当miR⁃93⁃5p的海绵,通过miR⁃93⁃5p/STAT3通路来调节炎症因子IL⁃6和IL⁃8的表达水平以及影响上皮细胞周期来调控上皮细胞的增殖。同时,用二氧化钛处理16HBE对circRNA 0039411的表达并无明显影响。circRNA与支气管上皮的炎症有一定的相关性,在不同的刺激原作用下,circRNA可能存在特异性的表达,不同的circRNA对支气管上皮炎症反应发挥促进或者抑制的不同作用,circRNA有望成为反映支气管上皮炎症及其严重程度的生物标志物。

  • 2.3 circRNA与miRNA网络

  • 近年来miRNA在转录后水平调控基因表达的机制较为明确。miRNA是一种长度约20~25个核苷酸的具有调控功能的非编码RNA,与靶基因mRNA的3′⁃UTR区域碱基互补配对,进而抑制靶基因的表达[27]。许多研究表明miRNA与哮喘关系密切,可作为哮喘的诊断指标,也可预测哮喘的严重程度,例如miRNA⁃21通过靶向10号染色体上的磷酸酶和张力素同源物抑制PI3K⁃AKT通路,促进气道平滑肌细胞增殖,参与气道重塑,同时血清中miRNA⁃21表达水平对类固醇敏感和类固醇抵抗型儿童哮喘的鉴别具有预测价值。miRNA⁃155和let⁃7miRNA有助于儿童哮喘的诊断及严重程度的预测等[28-32]。部分非编码RNA能够通过竞争性与miRNA结合形成miRNA反应元件,从而减弱miRNA对靶基因的负性调控,也称ceRNA机制[33-35]。目前,关于circRNA在哮喘中的直接研究较少,但是上述很多研究表明circRNA可能通过ceRNA机制参与哮喘的发生发展。发挥这类竞争性交互作用的circRNA大多为ecircRNA,它由一个或多个外显子环化而成,在细胞质内有一定丰度且稳定存在,具有物种保守性及组织特异性,但具有miRNA结合位点的ecircRNA只占少数,并且只有当ecircRNA与miRNA的表达水平处于近似数量级时,这种竞争性的交互作用才不会被弱化[36]。由屋尘螨诱导构建的哮喘小鼠模型中鉴定了280个差异表达的circRNA,利用miRanda算法预测构建circRNA⁃miRNA互作网络,提示差异表达的circRNA可能与miRNA竞争性结合,通过“自身免疫性疾病”“细胞黏附分子”和“吞噬作用”等过程参与哮喘的发生[37]。Shang等[38] 研究发现用脂多糖处理的巨噬细胞与脂肪源性干细胞分泌的外泌体共培养,过表达mmu_circ_0001359可以通过海绵miR⁃183⁃5p靶向FoxO1转录因子促进M1型巨噬细胞向M2型巨噬细胞转化,抑制气道炎症反应,减轻气道重塑。circHIPK3能够作为miR⁃326的海绵,靶向基质相互作用分子1(stromal interaction molecule1, STIM1)调节气道平滑肌细胞的增殖、迁移及凋亡参与哮喘的气道重塑[39]。Huang等[40] 对哮喘患者CD4+ T细胞进行微阵列分析发现了有597个差异表达的circRNA,hsa_circ_0005519在哮喘患者CD4+ T细胞中上调变化≥3.7倍。随后另一个样本中通过实时荧光定量PCR、荧光素酶报告试验、干扰等方法发现hsa_circ_0005519可以通过海绵吸附hsa⁃let⁃7a⁃5p来上调IL⁃6和IL⁃13的表达。该研究发现哮喘患者CD4+ T细胞中高表达的hsa_circ_0005519与较高水平的呼出气一氧化氮(fractional exhaled nitric oxide, FeNO)、外周血嗜酸性粒细胞比例相关。hsa_circ_ 0002594在哮喘患者CD4+ T细胞中高表达,且在有哮喘高危因素的人群中有相对更高的表达,经皮质类固醇激素治疗后hsa_circ_0002594表达降低[41]。上述研究表明circRNA可能成为哮喘诊断和治疗的潜在生物标志物。在很大程度上circRNA在哮喘发生发展过程中的作用还不明确,大样本的验证研究相对较少。但随着高通量技术及生物信息学技术的高速发展,以ceRNA机制作为理论依据构建cir⁃ cRNA⁃miRNA互作网络也许可以为哮喘表观遗传学研究提供更清晰、有脉络的参考。

  • 3 总结与展望

  • circRNA在真核生物体内广泛稳定存在且保守性较高,其在骨关节炎、类风湿性关节炎、糖尿病等慢性炎症性疾病中发挥着重要的作用[42-44]。目前许多研究表明circRNA参与了哮喘的发病过程,如调控免疫反应、支气管上皮炎症反应以及气道重塑过程等,对哮喘的预防、诊断、治疗均有重要意义,但目前尚缺乏相关的临床研究评估circRNA与哮喘患者临床数据的相关性。circRNA通过海绵吸附miRNA调控靶基因的表达只是其发挥作用的一种机制,circRNA的其他生物学功能是否参与哮喘的发病仍需更多针对性的研究。随着不断深入地研究,circRNA有望成为哮喘诊断标志物及治疗的新靶点。

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  • 参考文献

    • [1] HANSEN T B,JENSEN T I,CLAUSEN B H,et al.Natu⁃ ral RNA circles function as efficient microRNA sponges [J].Nature,2013,495(7441):384-388

    • [2] LIU J,LIU T,WANG X M,et al.Circles reshaping the RNA world:from waste to treasure[J].Mol Cancer,2017,16(1):58

    • [3] LIU C X,LI X,NAN F,et al.Structure and degradation of circular RNAs regulate PKR activation in innate immunity [J].Cell,2019,177(4):865-880

    • [4] SUN J,WANG X,WANG D,et al.circAtp9b knockdown alleviates LPS⁃caused inflammation provided that microR⁃ NA⁃27a is upregulated[J].Int Immunopharmacol,2020,78:105925

    • [5] JECK W R,SORRENTINO J A,WANG K,et al.Circular RNAs are abundant,conserved,and associated with ALU repeats[J].RNA,2013,19(2):141-157

    • [6] SUZUKI H,ZUO Y,WANG J,et al.Characterization of RNase R ⁃ digested cellular RNA source that consists of lariat and circular RNAs from pre ⁃ mRNA splicing[J].Nucleic Acids Res,2006,34(8):e63

    • [7] SALZMAN J,CHEN R E,OLSEN M N,et al.Cell ⁃type specific features of circular RNA expression[J].PLoS Genet,2013,9(9):e1003777

    • [8] XIAO M S,AI Y,WILUSZ J E.Biogenesis and functions of circular RNAs come into focus[J].Trends Cell Biol,2020,30(3):226-240

    • [9] LI Z,HUANG C,BAO C,et al.Exon ⁃ intron circular RNAs regulate transcription in the nucleus[J].Nat Struct Mol Biol,2015,22(3):256-264

    • [10] ABDELMOHSEN K,PANDA A C,MUNK R,et al.Identi⁃ fication of HuR target circular RNAs uncovers suppres⁃ sion of PABPN1 translation by CircPABPN1[J].RNA Bi⁃ ol,2017,14(3):361-369

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    • [12] WANG Y,WANG Z.Efficient backsplicing produces translatable circular mRNAs[J].RNA,2015,21(2):172-179

    • [13] YANG Y,FAN X,MAO M,et al.Extensive translation of circular RNAs driven by N6 ⁃ methyladenosine[J].Cell Res,2017,27(5):626-641

    • [14] CHEN Q,MANG G,WU J,et al.Circular RNA circSnx5 controls immunogenicity of dendritic cells through the miR ⁃ 544/SOCS1 axis and PU.1 activity regulation[J].Mol Ther,2020,28(11):2503-2518

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    • [17] CHEN Y G,CHEN R,AHMAD S,et al.N6 ⁃ methyl⁃ adenosine modification controls circular RNA immunity [J].Mol Cell,2019,76(1):96-109.e9

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    • [28] ELBEHIDY R M,YOUSSEF D M,EL ⁃SHAL A S,et al.MicroRNA ⁃21 as a novel biomarker in diagnosis and re⁃ sponse to therapy in asthmatic children[J].Mol Immu⁃ nol,2016,71:107-114

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    • [30] POLIKEPAHAD S,KNIGHT J M,NAGHAVI A O,et al.Proinflammatory role for let ⁃7 microRNAS in experimen⁃tal asthma[J].J Biol Chem,2010,285(39):30139-30149

    • [31] YU Z W,XU Y Q,ZHANG X J,et al.Mutual regulation between miR ⁃ 21 and the TGFβ/Smad signaling pathway in human bronchial fibroblasts promotes airway remodel⁃ ing[J].J Asthma,2019,56(4):341-349

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