Advances in Clinical Medicine
Vol.
13
No.
05
(
2023
), Article ID:
65181
,
7
pages
10.12677/ACM.2023.1351034
miR-125a-5p与肺结核关系的研究进展
刘荣1,久太2*
1青海大学研究生院,青海 西宁
2青海大学附属医院,青海 西宁
收稿日期:2023年4月9日;录用日期:2023年5月3日;发布日期:2023年5月12日
摘要
肺结核(pulmonary tuberculosis, PTB)指的是由结核分枝杆菌引发的肺部感染性疾病,是严重威胁人类健康的疾病。结核分枝杆菌感染后绝大多数感染者处于结核分枝杆菌潜伏感染(Latent tuberculosis infection, LTBI)状态,5%~10%的LTBI者一生中会发展为活动性结核病。miR-125a-5p是一种微小RNA分子亚型,研究显示miR-125a-5p对肺结核的发生发展及转归具有重要作用。本文介绍了miR-125a-5p调控巨噬细胞极化及炎症反应,总结了miR-125a-5p与肺结核的关联性,认为miR-125a-5p对肺结核患者的诊治有一定指导意义。
关键词
肺结核,潜伏期肺结核,miR-125a-5p,巨噬细胞,炎症反应
Research Progress on the Relationship between miR-125a-5p and Pulmonary Tuberculosis
Rong Liu1, Tai Jiu2*
1Graduate School of Qinghai University, Xining Qinghai
2Affiliated Hospital of Qinghai University, Xining Qinghai
Received: Apr. 9th, 2023; accepted: May 3rd, 2023; published: May 12th, 2023
ABSTRACT
Tuberculosis (pulmonary tuberculosis, PTB) refers to the pulmonary infectious disease caused by Mycobacterium tuberculosis, which is a serious threat to human health disease. After mycobacterium tuberculosis infection, the vast majority of infected people are in the latent mycobacterium tuberculosis infection (Latent tuberculosis infection, LTBI) status, and 5% to 10% of LTBI patients will develop active TB during their lifetime. As miR-125a-5p is a tiny RNA molecular subtype, studies showed that miR-125a-5p plays an important role in the development and outcome of pulmonary tuberculosis. This paper introduces the regulation of macrophage polarization by miR-125a-5p and inflammatory response, summarizes the association of miR-125a-5p and pulmonary tuberculosis, and believes that miR-125a-5p has some guidance for the diagnosis and treatment of pulmonary tuberculosis patients.
Keywords:Tuberculosis, Latent Tuberculosis, miR-125a-5p, Macrophages, Inflammatory Response
Copyright © 2023 by author(s) and Hans Publishers Inc.
This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).
http://creativecommons.org/licenses/by/4.0/
1. 引言
肺结核(pulmonary tuberculosis, PTB)是由结核分枝杆菌感染所导致的肺部感染性疾病,在世界范围内造成巨大的发病率和死亡率,据世界卫生组织(WHO)的估计,2021年全球新发结核病患者1060万名较2020年增加4.5%;全球160万人死于结核病,超过2020年和2019年死亡人数。中国2021年的肺结核新发病例数总计78.0万(2020年84.2万、2019年83.3万),发病率达55/10万(2020年59/10万),在世界30个结核病高负担国家中,中国的结核病发病率位居第3位,成为全球三大结核病高负担国家之一 [1] ,仍然是一个主要的全球健康问题。其引起肺组织的病理改变主要包括炎性渗出、增生以及干酪样坏死,经过抗结核治疗后大多数患者能够治愈。肺结核的发病机制可能与机体免疫反应存在一定的相关性,能够引发多种细胞因子随着单核巨噬细胞、活化的淋巴细胞浸润不断扩大,诱发炎症级联反应 [2] [3] 。因此,进一步研究炎症细胞因子水平变化,可为探讨肺结核感染发病机制提供新思路、新途径。此外,研究发现微小RNA (microRNA, miRNA)与多种疾病的形成和发展密切相关,如:肺结核、非典型性肺炎、乙型病毒性肝炎等 [4] 。miRNA与调控结核分枝杆菌感染炎症反应的致病机制具有密切关系 [5] 。miR-125a-5p是近年受到广泛关注的一个miRNA,其在肺癌、胃癌、食管癌等疾病中的作用机制已经日渐明朗,如miR-125a-5p和miR-125b水平在整个胃和食管致癌级联反应中均显著下调 [6] [7] 。但miR-125a-5p在结核感染及结核发病过程中如何发挥作用尚无系统的报告,本文就miR-125a-5p与肺结核的关系进行汇总阐述。
2. miRNA的分布、结构、生物学功能
miRNA可以从细胞、组织和体液中分离出来,如血清、血浆、眼泪或尿液 [8] 。miRNA是一类内源性非编码RNA,长度为21-24个核苷酸,来源于pri-miRNA和pre-miRNA [9] [10] 。miRNA作为转录后调节因子,通过与其3′-非翻译区(UTR)的特定序列的部分互补性,诱导靶基因的翻译抑制或降解来调节基因表达 [11] 由于miRNA是基因表达的关键调节因子,也是生物标志物开发的有希望的候选者。因此,对miRNA的研究正在扩大。miRNA被证明参与各种病理过程,并在疾病发生发展中发挥积极作用。miRNA与动物机体的免疫和炎症反应密切相关 [12] [13] 。Peng等 [14] 研究发现miRNA转录后可调控生物体内部分基因,其表达存在显著差异。同时,检测到肺结核患者血液中miRNA存在异常表达及具有寡核苷酸多态性,初步推测结核病与miRNA存在一定的关联。
3. miRNA调节结核感染后的免疫应答
结核分枝杆菌(Mycobacterium tuberculosis, MTB)经巨噬细胞表面的识别受体介导吞噬,当吞噬后,MTB抗原成分可刺激巨噬细胞产生白细胞介素1 (IL-1)、白细胞介素6 (IL-6)、肿瘤坏死因子α (TNF-α)、白细胞介素12 (IL-12)和各种趋化因子等,从而产生炎性反应 [15] ;在细胞因子作用下,树突状细胞和巨噬细胞被激活,表达共刺激因子加强抗原递呈和活化T细胞,启动适应性免疫。M1型巨噬细胞强大的促炎和抗原提呈能力,可诱导Th1细胞产生免疫反应,是机体抗感染、杀伤肿瘤细胞的免疫细胞 [16] [17] ,Sica等 [18] 发现M2型巨噬细胞具有免疫调节功能,诱导Th2细胞产生免疫反应。活化的Th1细胞通过分泌TNF-α和γ干扰素(IFN-γ)等细胞因子,从而进一步活化巨噬细胞,增加其杀菌的能力,而Th2细胞分泌细胞因子如白细胞介素4 (IL-4)和白细胞介素10 (IL-10),对抗结核免疫有负向调节作用 [19] 。病原体可通过调节几种miRNA下调炎症分子IFN-γ、TNF-α和人白介素受体相关激酶1 (IRAK1) [20] [21] [22] 。Rodriguez等 [23] [24] 认为miR-181a和miR-155对细胞活化后的免疫应答反应具有调节作用。因此,我们推测miR-125a-5p可能对结核感染后的免疫应答也具有调节作用,可抑制结核感染者肺泡巨噬细胞炎症反应。
4. miR-125a-5p调控巨噬细胞极化
病原体结核分枝杆菌具有顽强的能力,能够绕过宿主的免疫系统,最终实现自身优势。巨噬细胞是对结核分枝杆菌免疫非常重要的吞噬细胞之一,参与免疫系统识别吞噬并清除MTB的免疫应答过程。巨噬细胞具有异质性,其表型和功能受周围微环境的调节。巨噬细胞通常存在于两个不同的亚群中:1) M1型巨噬细胞具有促炎性,并被脂多糖(LPS)单独或与Th1细胞因子如IFN-γ、GM-CSF联合极化,并产生促炎细胞因子如白细胞介素-1β (IL-1β)、IL-6、IL-12、IL-23和TNF-α。2) M2型巨噬细胞,其具有抗炎和免疫调节作用,并被Th2细胞因子如IL-4和IL-13极化,并产生抗炎细胞因子如IL-10和TGF-β。M1和M2巨噬细胞具有不同的功能和转录谱,它们具有破坏病原体或修复炎症相关损伤的独特能力 [25] 。M1/M2巨噬细胞平衡极化决定了炎症或损伤中器官的命运。当感染或炎症严重到足以影响器官时,巨噬细胞首先表现出M1表型,释放TNF-α、IL-1β、IL-12和IL-23对抗刺激。但是,如果M1期持续下去,可能会导致组织损伤。因此,M2巨噬细胞分泌大量的IL-10和TGF-β来抑制炎症,有助于组织修复、重塑、血管生成,并保持体内平衡。
Graff等 [26] 在人巨噬细胞中发现miRNA在M1型巨噬细胞和M2型巨噬细胞中存在显著差异,miR-29b和miR-125a-5p这两个miRNA靶向抑制肿瘤坏死因子α诱导蛋白3 (TNF-a-induced protein 3, TNFAIP3)的表达从而使M1型巨噬细胞的标志物表达升高。因此,该研究表明miRNA影响巨噬细胞极化通路相关蛋白的表达水平,参与调控巨噬细胞极化过程。久太等 [27] 研究通过基因芯片PCR阵列检测结果显示:结核组较对照组高表达的基因有1种,低表达的基因有6种。感染组较对照组基因高表达有6种,低表达1种。按照数据分析所得的差异表达结果发现miR-125a-5p在肺结核活动期患者外周血中低表达,而在潜伏感染期患者外周血中高表达,提示其表达变化可能会影响巨噬细胞极化进而影响患者疾病状态。Cho等 [28] 研究发现,肺结核的多药耐药性与M2型巨噬细胞相关。刘艳华等 [29] 研究发现活动性肺结核患者单核巨噬细胞向M1型巨噬细胞极化能力减弱,而向M2型巨噬细胞极化能力增强。因此,若能选择性激活M1型巨噬细胞会激活机体免疫功能,从而杀伤结核分枝杆菌。总之,在肺结核的发生发展过程中,巨噬细胞发挥着关键性作用,miR-125a-5p可能调控巨噬细胞向M1型极化进而影响肺结核感染发病过程。
5. miR-125a-5p通过TLR-NFκB信号通路调控巨噬细胞炎性反应
机体感染MTB时诱导巨噬细胞产生炎症反应,巨噬细胞与结核分枝杆菌相互作用所致的炎性反应对结核病发生发展及转归具有重要作用。但该过程十分复杂,并受到多种信号调控。Sly等 [30] 研究表明,信号通路对多种感染性疾病的发生发展具有重要的调控作用,但其对结核分枝杆菌与巨噬细胞相互作用过程中导致的巨噬细胞炎症反应的调控机制尚未完全阐明。结核分枝杆菌感染巨噬细胞时首先通过与Toll样受体(TLR)结合,并与CD14和MD-2形成复合物。TLR的胞内部分有Toll/IL-1受体区域和肿瘤坏死因子受体相关因子(TRAF),这两个结构域能够结合信号通路的其它蛋白,最终激活NFκB信号通路,导致TNF-α、IL-1、IL-6、和IL-8等炎症因子的表达 [31] 。结核分枝杆菌感染巨噬细胞后通过结核分枝杆菌表面配体激活Toll样受体将信号传至髓样分化因子88 (MyD88)并经TRAF6激活NFκB通路,从而诱导巨噬细胞产生大量TNF-α和IL-6等炎性因子 [30] 。当炎性因子过度分泌会引起机体的强烈炎性反应,从而诱导机体细胞与组织的坏死,这时结核分枝杆菌会扩散并感染其他细胞。NFκB是一种转录因子,是参与调节免疫、炎症反应和细胞分化相关的基因,在炎症反应中具有重要作用 [32] [33] 。因此,炎性反应对结核分枝杆菌与巨噬细胞相互作用过程中,机体对结核分枝杆菌的免疫杀伤及巨噬细胞及结核分枝杆菌的命运均有重要的作用。炎性反应调控过程涉及多条信号通路,近年来研究发现NFκB信号通路在多种病原菌诱发的炎性反应过程中具有重要调控作用,但是目前关于这一重要过程的调控机制尚未完全阐明。
miRNA是小的非编码RNA分子,已成为巨噬细胞转录后调节的关键成分。这些分子可以通过与RNA分子内互补序列的碱基配对来沉默mRNA的翻译。据报道,该miRNA通过靶向Traf6、Irak1、Irak2、NFκB、Stat1和Ap1的mRNA,通过抑制TLR、NF-κB和STAT信号通路,抑制巨噬细胞的促炎反应 [34] [35] [36] [37] 。Rajasekaran等 [38] 研究证实,miRNA在减轻脓毒症肺损伤方面发挥至关重要的作用,例如:miR-146a能阻断肺泡巨噬细胞中TLRs/NF-кB通路上的人白介素受体相关激酶1 (IRAK-1)和肿瘤坏死因子受体相关因子6 (TRAF-6)基因,它减少炎症因子如TNF-a的产生,并对脓毒症小鼠具有肺保护作用 [39] 。miR-132增强胆碱能抗炎通路并抑制肺泡巨噬细胞炎症反应 [40] 。Li等 [41] 发现miR-223可以靶向IKK-a抑制核因子кB (NF-кB)并抑制巨噬细胞炎症反应。越来越多的证据表明,一些miRNA在结核分枝杆菌感染过程中发挥重要作用,主要通过调节免疫信号通路的输出。在这些途径中,NFκB途径是非常重要和经常参与的,TNF-α是NFκB途径的重要上游分子 [42] 。相关研究表明,miRNA-125a-5p能抑制NF-κB信号通路,降低炎症反应和细胞凋亡 [43] 。据报道,miR-125a-5p在TLR2/4信号传导后增加,并通过靶向NF-κB和KFL4信号传导途径在减少炎症细胞因子(IL-6、IL-12和TNF-α)的产生中发挥关键作用 [44] [45] [46] [47] 。Cai等 [48] 研究表明,过表达miR-125a-5p会降低TGF-β1和IL-6的产生,以及其下游靶点STAT3和Smad2/3的表达;相比之下,下调miR-125a-5p增加了TGF-β1和IL-6的产生。因此,深入研究TLR-NFκB信号通路对结核分枝杆菌与巨噬细胞相互作用过程中的炎性反应调控机制将可能对结核病的靶向药物研制均具有重要理论意义。
6. 小结及展望
综上所述,miRNA调控结核分枝杆菌感染后的免疫系统产生免疫应答,从而发挥相应的免疫调节功能。我们推测miR-125a-5p表达水平升高可能会调控了巨噬细胞M1型极化分泌促炎细胞因子,会激活机体免疫功能,从而杀伤结核分枝杆菌。miR-125a-5p调节巨噬细胞极化在炎症相关疾病中有治疗潜力,其可能成为潜伏期肺结核诊断和治疗靶点。同时,miR-125a-5p也可能通过靶向TLR-NFκB信号通路减少炎症细胞因子的产生,减轻炎症反应,避免了活动性肺结核的发生,为临床肺结核诊治提供新思路、新方向,值得进一步深入探究,但目前尚缺乏相关临床数据资料支持。未来应进一步探讨miR-125a-5p在肺结核发生过程中的具体机制,以期为肺结核的诊治提供更精确的方案。
基金项目
国家自然科学基金(2022-0301-ZJC-0108)。
文章引用
刘 荣,久 太. miR-125a-5p与肺结核关系的研究进展
Research Progress on the Relationship between miR-125a-5p and Pulmonary Tuberculosis[J]. 临床医学进展, 2023, 13(05): 7410-7416. https://doi.org/10.12677/ACM.2023.1351034
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