黏膜免疫是指机体与外界相通的胃肠道、呼吸道、泌尿生殖道等黏膜组织及某些腺体的局部免疫，由黏膜组织中的免疫组织、免疫细胞和免疫分子组成，其主要功能是清除经黏膜表面入侵机体的病原微生物。人体黏膜表面积巨大，是外界抗原直接接触的门户，也是机体抗感染的第一道防线。大量病原微生物入侵黏膜，触发宿主抗感染的固有免疫应答，引起局部炎症反应，导致黏膜屏障结构受损，外界病原微生物通过受损的黏膜屏障进入黏膜组织，激活大量固有免疫细胞，释放一系列炎性细胞因子，加重黏膜炎症反应，黏膜炎症又进一步损伤屏障功能，两者相互促进，最终导致黏膜相关组织损伤性病变。目前大部分感染性疾病的发生都与黏膜免疫失调密切相关，黏膜免疫应答失调进而导致黏膜炎症反应异常。miR-146a在黏膜免疫功能和炎症反应中发挥重要的调节作用。本文介绍miR-146a及其直接作用靶点，并讨论miR-146a对黏膜免疫应答以及黏膜炎症性疾病的调控作用。
1 miR-146a及其直接作用靶点miRNAs是一类进化上高度保守且广泛存在于真核生物中的一类内源性小分子单链非编码RNA，长度为19~25 nt，通过与靶mRNA的特异性结合，降解mRNA或阻碍其翻译，从而在转录后水平调控多种信号通路和生物过程[1]。miR-146a是miR-146家族(包括miR-146a和miR-146b)成员之一，miR-146a与其靶蛋白发挥作用依赖核因子-κB(Nuclear Factor Kappa-B, NF-κB)信号通路的调控[2]，miR-146a通过降低NF-κB和TLR4的活性，抑制NF-κB通路下游炎症因子白细胞介素(IL)-6、IL-1β和肿瘤坏死因子-α(TNF-α)等细胞因子的分泌[3]，在抑制炎症反应的加重和维持黏膜免疫稳态方面发挥重要作用。现有文献报道的miR-146a直接作用靶基因见表 1。
| 表 1 文献报道的miR-146a靶基因情况 |
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黏膜免疫具有固有免疫特性和适应性免疫特性，发生于黏膜表面和黏膜淋巴组织中的固有免疫应答不仅起到屏障保护和抑炎作用，还可启动适应性免疫应答。适应性免疫应答指机体受抗原刺激后，抗原特异性淋巴细胞识别抗原，发生活化、增殖、分化或失能、凋亡，进而显示生物学效应的全过程，可通过调控固有免疫细胞和分子在黏膜固有免疫应答中发挥重要作用，miR-146a在黏膜固有免疫应答和适应性免疫应答中均发挥重要调控作用。
2.1 miR-146a与黏膜固有免疫应答 2.1.1 miR-146a与黏膜屏障黏膜屏障由上皮层、黏液层、免疫活性物质及黏膜表面特征性分布的共生菌群等组成，完整的黏膜组织构成机体防御病原微生物入侵的第一道屏障，强大的屏障功能保护机体内表面，维持机体黏膜免疫稳态。
miR-146a在维持黏膜完整性和调控黏膜屏障功能方面发挥重要作用。Miyata等[4]研究发现，人鼻腔上皮细胞受聚肌苷酸-聚胞苷酸[plyinosinic-polycytidylicacid, Poly(I: C)]的刺激，通过TLR3介导的磷脂酰肌醇3激酶(phosphatidylinositol 3-kinase, PI3K)、c-Jun氨基末端激酶(c-JunN-terminal kinase, JNK)和NF-κB信号通路促使miR-146a表达升高，miR-146a靶向调控TNF受体相关因子6(TNF receptor-associated factor 6, TRAF6)促进紧密连接蛋白1(claudin 1)和连接黏附分子A (junctional adhesion molecule A, JAM-A)的表达，改善黏膜屏障的紧密连接。Hu等[34]研究表明经梅毒螺旋体刺激的巨噬细胞分泌包含miR-146a-5p的外泌体，靶向作用于连接黏附分子C(junctional adhesion molecule C, JAM-C)，从而降低人脐静脉内皮细胞通透性和单核细胞跨内皮迁移，保护黏膜屏障的完整性。He等[5]通过对大鼠缺血/再灌注(ischemia/reperfusion, I/R)模型的研究，确定miR-146a通过下调TLR4/TRAF6/NF-κB通路，改善大鼠小肠I/R损伤，保护肠黏膜屏障和黏膜组织免受炎症的破坏和损伤。以上数据表明miR-146a可促进紧密连接蛋白和连接黏附分子的高表达，降低黏膜通透性，维持屏障的完整性，从而抵御病原体入侵。
2.1.2 miR-146a与黏膜固有免疫细胞和分子免疫细胞和分子是固有免疫应答的主要成分，免疫分子还是抑菌、杀菌、启动和参与固有免疫应答的效应分子。
由IL-1β等促炎细胞因子介导的炎症反应促使miR-146a表达升高，miR-146a主要参与先天免疫，是协调免疫和炎症信号的最重要的一种miRNAs，在抑制炎症反应的加重和维持免疫稳态中发挥重要作用[41]。一但miR-146a的表达水平失调，则导致机体对低剂量炎症刺激的免疫反应耐受，进而发展为慢性炎症[42]。大鼠肺泡巨噬细胞(NR8383)中，曲古抑素A(trichostatin A, TSA)通过上调miR-146a的表达在体外急性肺损伤模型中发挥抑炎功能[43]。Vergadi等[44]研究表明在Akt2基因敲除的无菌性肺损伤的小鼠模型中，小鼠巨噬细胞通过miR-146a过表达抑制TLR4信号通路，从而促使其向M2抗炎表型分化，进而对肺损伤发挥显著保护作用。Duan等[10]研究表明骨髓间充质干细胞中富含miR-146a-5p的外泌体通过下调IRAK1和活化T细胞5的核因子(nuclear factor of activated T cell 5, NFAT5)的表达，降低神经元的凋亡以及促炎介质诱导型一氧化氮合酶(iNOS)、环氧合酶-2(COX-2)和单核细胞趋化蛋白1(MCP-1)等的释放量，抑制小胶质细胞M1或巨噬细胞极化相关的炎症反应，在脑出血后提供神经保护和功能改善。OVA诱导的小鼠骨髓来源性树突状细胞(bone marrow-derived dendritic cell, BMDC)过敏性炎症模型中，过表达的miR-146a通过靶向Notch1信号，抑制DCs表面成熟标志物CD80和CD86的表达，减少促炎细胞因子IL-12的分泌，增加抗炎性细胞因子TGF-β1和IL-10以及CD4+Th细胞中Foxp3的表达，从而诱导BMDCs的免疫耐受[45]。另外受IL-1β和TNF-α联合诱导的踝状突软骨细胞炎症模型中，炎症反应的保护因子miR-146a和肿瘤坏死因子受体OX40的同源配体OX40L在炎症环境中表达显著增加，骨关节炎中表达升高的miR-146a通过靶向调控OX40L抑制OX40的表达，减少MMP9、MMP13、COX2和ADAMTS5等炎症因子的表达，从而抑制炎症反应[23]。在胶质母细胞衍生的细胞系OCCM-30中，IL-1β诱导高表达的miR-146a-5p抑制炎症因子IL-6和L-1β的表达，缓解牙周炎症[46]。以上研究表明miR-146a不论是在固有免疫细胞还是免疫分子中都发挥重要的抑炎作用。
2.2 miR-146a与黏膜适应性免疫应答适应性免疫应答根据参与免疫应答、介导的免疫效应和细胞种类的不同可分为T细胞介导的细胞免疫和B细胞介导的体液免疫。近来有研究显示T细胞[47]和B细胞[35]介导的免疫应答激活皆与miR-146a表达的变化有关，表明miR-146a在机体适应性免疫调节中同样发挥重要调控作用。
T细胞介导的细胞免疫应答与miR-146a表达变化密切相关。Curtale等[47]发现miR-146a在初始T细胞中表达较低，而在记忆T细胞中大量表达，miR-146a通过靶向Fas相关死亡结构域蛋白(Fas-associated death domain, FADD)减少IL-2的分泌，进而调节活化诱导的细胞死亡(activation-induced cell death，AICD)，减少T细胞的凋亡，从而有助于调节适应性免疫反应。Lu等[25]研究表明miR-146a在调节性T细胞(regulatory T cell，Treg)中差异性表达，miR-146a靶向作用于干扰素-γ(IFN-γ)受体信号下游的信号转导与转录激活因子1(signal transducer and activator of transcription 1, STAT1)，控制IFN-γ介导的Th1免疫应答，而miR-146a缺失会导致免疫反应失调，使得Treg细胞无法抑制过度的免疫反应，从而导致严重的自身免疫性疾病。miR-146a作为一种重要的分子制动器，负向调控由自反应性CD4+T细胞自分泌的IL-6和IL-21所诱导的Th17分化途径，抑制自身免疫性疾病的发生和发展[48]。Zhou等[49]的研究同样肯定了miR-146a在调控Treg细胞功能中的作用，miR-146a在活动期类风湿性关节炎(rheumatoid arthritis, RA)患者中表达减少，导致Treg细胞表型改变，从而使RA患者出现异常的免疫反应和炎症反应，说明miR-146a在维持适度免疫反应中起重要作用。Emming等[50]研究表明初级T细胞中转录因子BHLHE40通过靶向抑制ZC3H12D等抑炎基因的表达，激活NF-κB信号通路，而高表达的miR-146a抑制NF-κB激活。Yang等[51]的研究成果与此结果一致，miR-146a通过调节NF-kB信号通路来抑制CD4(+)CD25(-)T(Tcons)细胞中IL-5和IL-13的表达，有效改善豚草花粉诱导的试验性小鼠过敏性结膜炎症状。另外RA患者CD4+T细胞中表达显著上调的miR-146a，通过下调Fas相关因子1(Fas-associated factor 1, FAF1)的表达，有效抑制T细胞的凋亡[52]。
B细胞介导的体液免疫应答同样受miR-146a表达变化的调控。Pratama等[35]研究表明miR-146a靶向作用于ICOS-ICOSL信号，限制T滤泡辅助(T follicular helper, Tfh)细胞和生发中心(germinal centre, GC)细胞的积累，限制GCs中的Tfh细胞数有利于GC中B细胞的选择和免疫耐受的维持，miR-146a主要通过调节GC B细胞中的CD40信号通路来控制GC反应，以产生针对广泛入侵微生物的强烈且持久的免疫反应，并防止不必要的自身免疫性疾病。另外Amrouche等[53]在肾小球肾炎为特征的自身免疫综合征的研究中发现，miR-146a-/-小鼠在衰老过程中产生自身免疫性疾病，这与小鼠肾脏和免疫细胞跨膜蛋白Kim1/Tim1表达缺陷而解除对调节性B细胞(Bregs)的管制有关。小鼠哮喘模型B细胞中过表达的miR-146a上调B细胞中免疫球蛋白类转换DNA重组的一个关键因素14-3-3σ的表达，进而增强B细胞抗体分泌和IgE类别转换，这表明miR-146a有助于抑制过敏性哮喘和其他IgE介导的过敏条件下的炎症[54]。以上研究虽表明了miR-146a在调控适应性免疫中的重要作用，但具体机制或许还需要进一步的研究。黏膜免疫在机体维持针对有害抗原的保护性免疫应答与免疫稳态之间的平衡中发挥重要作用，而异常的免疫应答可导致黏膜炎症和黏膜相关的自身免疫性疾病。
3 miR-146a对黏膜炎症性疾病的调控作用近来研究表明促炎细胞因子IFN-γ、TNF-α和IL-1β的混合物可诱导人视网膜上皮细胞(HRPE)、人气道平滑肌细胞(hASMCs)和血浆中miR-146a高表达，升高的miR-146a靶向作用于IRAK1负向调控NF-κB通路，进而抑制视网膜退行性疾病的炎症反应[11, 37, 55]。此外miR-146a对炎症性肠病(inflammatory bowel disease, IBD)[56]和I/R损伤[38]也有一定的预防和治疗潜力。Mirzakhani等[57]研究显示miR-146a与IBD疾病活性指数呈负相关，miR-146a在人IBD外周血单个核细胞中表达降低，而在狗IBD的结肠黏膜和血清中表达反而显著增加[58]，这表明miR-146a在患有IBD的不同物种体内差异性表达。Guz等[22]深入研究发现，由于霍乱弧菌衍生的膜外囊泡富含miR-146a，结肠癌上皮细胞系T84细胞在霍乱弧菌溶细胞素的刺激下，高表达的miR-146a靶向下调IRAK2，降低IL-8、TNF-α、CCL20和IL-1β的表达，降低先天免疫防御反应的强度，从而缓解结肠黏膜炎症反应。miR-146a在慢性胃炎中同样发挥重要调控作用。2010年Liu等[59]研究首次发现幽门螺杆菌(Helicobacter pylori，H. pylori)感染正常胃上皮细胞系GES-1细胞所引起的炎症反应中，miR-146a作为新的负调节因子通过靶向下调IRAK1和TRAF6的表达，降低NF-kB活性，从而减少IL-8、GRO-a和MIP-3a的分泌。受H. pylori感染的人胃癌细胞系SGC7901细胞中，高表达的miR-146a以同样的方式抑制由IL-17A所引发的炎症反应[60]。Liu等[36]的研究进一步发现受H. pylori感染的GES-1细胞中，miR-146a通过靶向结合并降解其另外一个靶基因前列腺素内过氧化物合酶2 (PTGS2)，降低H. pylori感染诱导的胃黏膜上皮细胞中PTGS2蛋白的表达，从而缓解炎症。以上研究均表明miR-146a在H. pylori感染导致的慢性胃炎中发挥抑炎作用，同时也提示miR-146a在不同细胞系中可靶向调控相同的蛋白发挥相似的生物作用，亦可在相同的细胞系中靶向调控不同蛋白发挥相同的生物作用。
miR-146a除了在以上眼部和胃肠道黏膜炎症中发挥重要作用外，还可调控多种呼吸道和泌尿生殖系统黏膜炎症。Yan等[20]利用人中性粒细胞弹性蛋白酶刺激人鼻窦上皮细胞建立的慢性鼻窦炎细胞模型中，miR-146a可通过靶向抑制表皮生长因子受体(EGFR)的激活，逆转鼻窦炎患者黏蛋白MUC5AC分泌过多的现象。暴露于颗粒物(PM)可导致多种心肺疾病，PM 1激活NF-κB信号通路，诱导人肺支气管上皮细胞(BEAS-2B)[6]的炎症反应，慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)患者在人工通气过程中产生的振荡压力引起人原代肺上皮细胞(HSAEpCs)[7]的炎症，这两种细胞受炎症刺激高表达的miR-146a靶向调控IRAK1和TRAF6，抑制NF-κB信号通路的激活，从而缓解肺部炎症和损伤。除HSAEpCs，COPD患者的成纤维细胞的炎症反应同样受miR-146a的调控，miR-146a靶向降低COX-2的表达，减少促炎细胞因子和前列腺素(PG) E2的产生，有利于成纤维细胞修复功能的恢复和肺部炎症的缓解[61]。哮喘患者人气道平滑肌细胞(HASMCs)中miR-146a同样靶向作用于COX-2，负向调节IL-1β和RNA结合蛋白HuR的表达，缓解哮喘症状[37]。以上研究表明miR-146a在肺部不同的细胞中发挥相同的抑炎作用。此外，miR-146a还参与泌尿生殖系统黏膜炎症的调控，子宫内膜炎性病变引起的蜕膜细胞因子微环境的不平衡与自然流产(spontaneous abortion, SA)的发病机制密切相关，miR-146a-5p可靶向下调TRAF6、IRAK1、CCL5和CD80表达，进而改善蜕膜细胞因子的微环境[12]，为SA的治疗提供了新的治疗靶点。
miR-146a不仅调控多种黏膜炎症性疾病，对系统性红斑狼疮(systemic lupus erythematosus, SLE)等黏膜相关的自身免疫性疾病中也同样发挥重要的抑炎作用。Qu等[62]在I型IFN和LPS诱导THP-1细胞建立的SLE细胞炎症模型中发现，I型IFN促进了LPS诱导的MCP-1的产生，在转录后水平抑制miR-146a的表达，进而导致SLE患者免疫耐受的丧失和炎症反应的过度激活。Karrich等[63]研究发现在受TLR7/9刺激的浆细胞样树突细胞(plasmacytoid dendritic cell, PDC)中miR-146a的高表达抑制促炎细胞因子的产生，降低了pDCs的存活率，从而减少IFN-α/β的分泌，缓解SLE的自身免疫状况。干扰素调节因子5(interferon regulatory factor-5, IRF5)和STAT1作为影响SLE病程的另外两个重要因素，miR-146a不仅可靶向作用于IRF5和STAT1影响IFN信号转导，还可靶向下调巨噬细胞中TRAF6、IRAK1和IRAK2的表达，进而抑制I型IFN的产生，缓解SLE的病程发展[64]。
4 总结与展望本综述强调了miR-146a对黏膜免疫应答反应以及黏膜炎症的调控作用，以及对黏膜炎症性疾病的潜在治疗作用。体外和体内试验均表明，受miR-146a调控的黏膜炎症和黏膜相关的自身免疫病，大部分以miR-146a作用靶点及其调控机制作为切入点以达到治疗目的，当前这一疗法已被广泛用于药物研究。最新报道[65-66]显示IRAK1、IRAK4或IRAK1/4抑制剂是SLE和RA治疗的必要手段，不仅能减轻疾病的症状，还能降低微生物感染的风险。另外一种选择性抗IRAK1活性的药物SB1578，在小鼠胶原诱导的关节炎模型中已被证明具有显著的抑炎作用[67]。对于目前的研究现状，针对发病机制采取局部用药或是针对miR-146a靶蛋白的上游进行控制或许是个很好的思路。未来的研究可能会揭示更多新的miR-146a治疗靶点，为新疗法的开发提供更充分的理论依据，使miR-146a有望成为预防、检测、治疗、监控和诊断黏膜免疫相关疾病及判断疾病预后的生物标志物，为各种发病机制、靶向特异性治疗及改善预后等提供新的探索方向。
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