α- 硫辛酸的免疫调节作用

郭 娟 刘 玮 李胜光

(解放军总医院第一附属医院风湿科，北京 100048)

α- 硫辛酸(α- Lipoic Acid，ALA)是由线粒体生成的二硫酚化合物，广泛存在于动植物体内。在生理状态下，人体内的ALA作为线粒体丙酮酸脱氢酶和α- 酮戊二酸脱氢酶复合物的辅酶，保护线粒体免受氧化攻击。ALA是硫辛酸的氧化态，双氢硫辛酸是硫辛酸的还原态，两者组成一对强力的氧化还原对。它们能够直接清除众多活性氧自由基(Reactive oxygen species ，ROS)，作为金属螯合剂减轻重金属离子对机体的氧化损伤；还能参与体内其他抗氧化剂的再生，因而被誉为“万能抗氧化剂”，且ALA及双氢硫酸较好的水溶性和脂溶性使其在细胞内外发挥抗氧化作用[1,2]。

基于其强有力的抗氧化功能和良好的安全性，ALA被广泛应用于糖尿病及其并发症、神经性疾病和心血管疾病。随着相关研究的不断深入，我们对ALA的作用机制有了更多的认识，包括保护胰岛细胞，增加胰岛素敏感性，加快神经传导及改善血管内皮功能[3]。除此之外，越来越多的实验数据提示ALA可能具有免疫调节作用。

近年来，氧化应激在某些自身免疫疾病发生发展中的作用获得普遍认可。研究已证实ROS与免疫系统交互影响：一方面，ROS几乎在每一种免疫细胞的信号传导中发挥着生理作用。如巨噬细胞分泌ROS发挥抗菌作用；调节性T细胞(Treg)通过释放ROS抑制其他T细胞的功能等[4]。另一方面，免疫细胞发生病理性改变时产生过量的ROS，加剧炎症和免疫系统进一步失衡。如氧化应激是系统性红斑狼疮(Systemic lupus erythematosus,SLE)普遍存在的病理状态[5]，促进免疫紊乱的发生；而免疫紊乱则进一步加剧氧化应激水平，两者共同参与了SLE的发生和发展。体外实验发现系统性硬化症皮肤成纤维细胞硫辛酸及硫辛酸合成酶含量减低[6]，DHLA可逆转皮肤纤维化发生。由此可以推测，抗氧化剂可用于治疗某些自身免疫性疾病，前者在清除ROS的基础上，极可能发挥免疫调节作用。通过文献复习，笔者对ALA的免疫调节的证据和可能机制进行综述。

1 ALA对免疫系统的调节功能

1.1T细胞 多发性硬化(Multiple sclerosis，MS)是中枢神经系统(Central nervous system,CNS)的自身免疫病，以机体出现髓鞘特异性T细胞并通过血脑屏障进入CNS长期生存为特征。实验性自身免疫性脑脊髓炎(EAE)是MS最常用的动物模型。多项研究发现使用ALA干预EAE建模过程，能够减少病变部位炎症细胞浸润，减轻疾病的严重程度[7- 9]。最近，Wang等[8]证实ALA减少EAE病变组织的Th17和Th1细胞数量，增加脾脏Treg细胞数量，提示ALA对T细胞分化和增殖的免疫调节作用。另有实验证实ALA上调高脂饮食小鼠空肠T细胞分化相关基因的表达，并使其恢复到正常水平(syk、CD86、CD28、CD2和CD25)，充分提示ALA参与调控T细胞的分化过程[10]。研究报道ALA能够通过激活人外周血T细胞前列腺素受体EP2和EP4增加cAMP合成[11]，导致IL- 2及IL- 2Rα(CD25)表达的减少，继而影响T细胞的增殖及激活[12]。

更多的研究提示ALA从多种途径调节T细胞的功能：ALA能够改善AIDS患者CD4+T细胞受损的线粒体功能[13]；下调人外周血T细胞表面CD4表达[14]；抑制CD4+T细胞分泌IFN- γ和IL- 4从而减轻特应性皮炎小鼠皮损的严重程度[15]。

除影响T细胞的增殖、分化和分泌功能，ALA还能够抑制T细胞的迁移功能。Ying等[16]的研究发现在渡边兔动脉粥样硬化模型中，ALA干预后T细胞对趋化因子的反应下降，进而减少了动脉粥样硬化斑块中的T细胞浸润。另有研究提示ALA抑制以下免疫细胞的迁移活动：EAE小鼠T细胞、EAE大鼠淋巴细胞和单核细胞、Jurkat细胞[9，17，18]。相关的机制研究提示迁移功能的抑制与ALA下调T细胞表面的极迟反应抗原4表达，并抑制微环境中的基质金属蛋白酶9活性[18]。

1.2B细胞 高脂饮食小鼠表现为免疫细胞数量减少和功能下降。基因表达谱研究提示：(1)高脂饮食可下调小鼠空肠B细胞受体(B cell receptor,BCR)的信号通路基因(CD19、Cr2、Ighg和Igh- 6)的表达，ALA干预后这些基因明显上调，其中Ighg甚至恢复正常水平[10]；(2)高脂饮食促进脾脏细胞凋亡，在ALA干预后获明显改善[19]。高脂饮食可同时减少外周血B细胞数量，ALA的治疗作用可能与上调脾脏 BCR信号通路相关基因的表达水平(Fos、Akt3、Pi3k、Rac1、Igh- 6、Ighg)有关[20]。这一系列实验证实ALA参与B细胞的增殖、凋亡及功能的调控。

1.3固有免疫细胞(NK细胞、巨噬细胞和单核细胞) 天然杀伤细胞(NK cell)的功能主要由细胞毒作用和细胞因子的分泌组成：前者与溶酶体酶的释放有关；后者以IFN- γ分泌为代表，IFN- γ是巨噬细胞的强力激活剂。ALA能够抑制IL- 12/IL- 18介导的人NK细胞的IFN- γ分泌和细胞毒性，通过依赖或者不依赖G蛋白偶联受体(GPCRs)的方式增加细胞内cAMP的生成[21,22]℃AMP诱导生成的PGE2能够抑制IL- 15介导的NK细胞的细胞毒性和IFN- γ分泌[23]。因此，ALA能够从多个方面抑制NK细胞的功能。

研究者发现ALA通过直接和间接的方式调控巨噬细胞的活化、吞噬和迁移功能：ALA抑制EAE小鼠巨噬细胞吞噬髓磷脂[24]，减少自身抗原的递呈；减少肥胖胰岛素抵抗小鼠内脏脂肪组织的巨噬细胞浸润和激活，抑制巨噬细胞分泌TNF- α和MCP- 1[25]，减轻内脏脂肪组织炎症。ALA通过Nrf2信号通路上调单核细胞的血红色氧合酶- 1(HO- 1)表达，继而抑制细胞因子的分泌[26]。还能够通过抑制单核细胞的迁移功能并稳定血脑屏障内皮的功能而减轻EAE大鼠的中枢神经炎症细胞浸润[9]。

2 ALA免疫调节的潜在靶点

ALA已经广泛运用于临床数十年，积累了大量的实验数据，根据相关的实验结果分析，笔者提出下列ALA免疫调节的潜在靶点。

2.1线粒体跨膜电位(mitochondrial membrane potential，ΔΨm) 线粒体是细胞的能量站，为三羧酸循环和氧化磷酸化提供场所，并参与细胞分化、调控细胞生长周期和细胞死亡。ΔΨm的稳定有利于维持细胞的正常生理功能。电子传递链和ATP合酶维持的线粒体内膜两侧的电化学梯度产生ΔΨm，因此ΔΨm、ATP和ROS三者的水平密切相关[27]。线粒体通透性转变孔(mPTP)是位于线粒体内外膜上的一组蛋白复合体，为非特异性通道，能维持ΔΨm及细胞内外的离子平衡：mPTP过度开放，ΔΨm出现不可逆地降低直至耗尽，诱导细胞凋亡或坏死[28]。生理状态下，T细胞的激活或凋亡早期出现一过性可逆转的ΔΨm升高即线粒体过级化(MHP)[29]；但SLE患者T细胞中MHP持续存在，导致ROS升高和ATP耗竭：一方面，MHP和ATP耗竭促进T细胞坏死，继而激活巨噬细胞和树突状细胞加剧炎症[30]；另一方面，ROS水平升高促进T细胞自发凋亡及IL- 10的释放[31]。T细胞凋亡的增加导致自身抗原的释放和疾病活动；而IL- 10水平上升进一步诱导T细胞凋亡并促进B细胞过度活化[32- 35]。研究证明在一定的浓度范围内，ALA和DHLA促进大鼠肝细胞线粒体mPTP开放[3,36]。因此，推测 ALA可能从多个方面改善SLE的线粒体功能失调，开放mPTP降低ΔΨm，改善SLE患者T细胞病理性的MHP；直接中和ROS，进而纠正T、B细胞的功能失调。

2.2哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin，mTOR)信号通路 mTOR是一种丝氨酸/苏氨酸激酶，和不同蛋白质结合，可形成2种不同复合物，即mTOR复合物1(mTOR complex 1，mTORCl)和mTORC2。mTORC1广泛存在于各种生物细胞，在调节细胞生长和代谢的过程中起到非常重要的作用[37]。

在细胞质中，mTORC1是许多信号级联反应共同的中间环节，生长因子、ATP/ADP水平、血糖、氧含量、TNF- α、基因毒应激和Wnt等信号转导通路通过多种途径调控mTORC1活性：其中激酶Ras/Erk、PI3K/Akt和IKKβ为正向调控，而Dsh/GSK3和LKBl/AMPK为负向调控。mTORC1激活后抑制细胞自噬功能；通过磷酸化真核细胞翻译起始因子4E结合蛋白1和核糖体S6蛋白激酶1促进蛋白质合成；通过活化转录因子固醇调节元件结合蛋白1(SREBP1)和过氧化物酶体增殖物激活受体γ(PPARγ)促进脂质合成；通过活化过氧化物酶体增殖物激活受体γ 辅助活化因子- 1α(PGC1- α)调控线粒体的氧化代谢和生物合成[38]。研究发现，位于线粒体外膜mTORC1与mPTP蛋白相连，通过感受ΔΨm的变化，单独发挥调控线粒体代谢的功能；抑制mTORC1活性可以降低线粒体氧耗、ATP合成和ΔΨm[39，40]。

生理状态下，mTORC1信号通路在免疫系统中发挥重要调节作用，影响大部分固有免疫细胞和适应性免疫细胞的细胞发育和功能[41]。激活的mTORC1信号通路保证树突状细胞、巨噬细胞和中性粒细胞TLR的病原体识别功能；阻断mTORC1信号通路损害固有免疫细胞功能，如树突状细胞的分化、抗原摄取、成熟和迁移，巨噬细胞的吞噬和趋化性，NK细胞的增殖和细胞毒性。在适应性免疫应答中，激活的mTORC1分子对于维持T细胞和B细胞的稳定和活化意义重大，并促进初始CD4+T细胞向Th1和Th17分化；抑制mTORC1活性则促进初始CD4+T细胞向Treg分化[42,43]，也促使初始CD8+T细胞向记忆性CD8+T细胞分化。

研究表明多种自身免疫病的发病可能与免疫系统的mTORC1信号通路过度激活相关：1型糖尿病、MS、SLE和类风湿关节炎(RA)[44- 48]。 mTORC1特异性抑制剂雷帕霉素改善1型糖尿病病情，与增加Treg数量并增强其抑制功能有关[49,50]。SLE患者T细胞的mTORC1过度激活，阻断CD4+CD25+T细胞的FOXP3表达，导致SLE患者Treg细胞数量和功能的下降[51- 54]。mTORC1过度激活也引起CD3+CD4-CD8-T cells双阴性T细胞坏死和IL- 4分泌增加，IL- 4导致SLE患者CD25+CD19+B细胞(Breg)几乎消失殆尽[52]，而Breg抑制CD4+效应性T细胞增殖，上调Treg细胞FOXP3和CTLA- 4的表达[55]。雷帕霉素治疗SLE初显成效[5,47]，除改善上述异常外，它还降低SLE患者T细胞基线和TCR激活后的胞内钙离子的水平[56]。但雷帕霉素不能改善SLE患者T细胞MHP状态，反映了其对T细胞线粒体功能失调治疗的局限性。IL- 22刺激RA患者的滑膜细胞增殖，与 PI3K/Akt/mTORC1信号通路激活相关[57]；抑制该通路减轻滑膜细胞的侵袭性[58]。在人TNF转基因小鼠的关节炎中，mTORC1信号通路促进滑膜破骨细胞的形成和活化，导致骨侵蚀和软骨破坏；RA患者破骨细胞mTORC1信号通路处于活化状态[48]，mTORC1抑制剂联合甲氨蝶呤治疗能够改善RA患者病情[59]。虽然雷帕霉素能够特异抑制mTORC1改善上述自身免疫病病情，但是它与FK506相似的副作用可能成为临床应用的障碍。

研究表明，ALA能够在不同的病理状态下，干预多种组织细胞mTORC1上游激酶的活性[1]。

2.2.1IKKβ、Ras/Erk1/2和PI3K/Akt和正向调控mTORC1 在RA患者成纤维样滑膜细胞和人脐静脉内皮细胞，ALA能够阻断TNF- α诱导IKKβ/NF- κB信号通路[60,61]。研究表明在肿瘤细胞和胰岛素抵抗小鼠， TNF- α通过激活IKKβ正向调控mTORC1通路[62,63]。因此，推测ALA可能通过阻断IKKβ激酶活性对mTORC1的活性产生负向调节作用。

研究表明ALA阻断Erk通路，改善动脉粥样硬化损伤并抑制血管平滑肌细胞增殖[64]；改善血管紧张素Ⅱ对血管平滑肌细胞的氧化应激损伤[65]；下调糖化血红蛋白介导的小鼠巨噬细胞NF- κB和TGF- β1的表达[66]。ALA抑制小鼠系膜细胞5羟色胺(5- HT)和生长因子对Erk1/2的激活；减少肾小球肾炎小鼠肾脏促纤维因子TGF- β1表达，并阻断系膜细胞向肌成纤维细胞转化[67，68]。ALA通过抑制Akt/S6K1和Erk活性减少促纤维化细胞因子(PDGF和TGF- β)对肝星状细胞的激活和氧化应激损伤，改善硫代乙酰胺诱导的大鼠肝硬化病情[69]。

ALA对于小鼠成纤维细胞的Erk1/2激酶具有双向调节作用，取决于细胞培养液中是否含有血清[70,71]，这在一定程度上可以解释ALA在不同的病理状态下对同一激酶出现不同调控方向。

ALA通过激活大鼠胰岛素细胞的Akt激酶减少过氧化氢介导的细胞凋亡[72]。ALA可以通过激活Akt并抑制Erk，起到减少TNF- α和游离脂肪酸对大鼠骨骼肌细胞造成氧化应激损伤[73]。近期临床研究观察到，2型糖尿病患者长期补充ALA可改善胰岛素刺激的葡萄糖氧化和糖原合成，发挥降低胰岛素水平及游离脂肪酸的作用[74]。

ALA抑制PI3K/Akt通路发挥抗肿瘤作用：抑制人乳腺癌细胞生长、促进肿瘤细胞凋亡；诱导人肝癌细胞凋亡[75，76]。ALA也通过抑制PI3K/Akt通路改善糖脂代谢失衡：下调小鼠脂肪细胞瘦素表达、抑制转录因子Sp1活性[77]；改善糖尿病大鼠的胰岛素抵抗[78]。

然而，ALA激活Akt通路也介导多种细胞保护作用，如阻断内质网应激介导的大鼠甲状腺细胞凋亡[79]，改善布比卡因、β- 淀粉样肽和过氧化氢对大鼠神经元的损害，改善缺血再灌注、TNF- α和游离脂肪酸对大鼠骨骼肌细胞造成氧化应激等，改善过氧化氢介导的大鼠胰岛素细胞凋亡，改善内毒素血症导致的心功能不全、血管内皮功能不全，单核细胞活化和急性炎症反应[72,73,79- 84]。

2.2.2AMPK(负向调控mTORC1) ALA激活AMPK，上调白色脂肪组织分泌脂联素改善高脂饮食大鼠的胰岛素抵抗[85]；下调促纤维化细胞因子表达、减少胶原沉积改善糖尿病大鼠心肌病变[86]；促进自发性高血压大鼠血管舒张[87]；上调人肝细胞的脂肪组织甘油三酯水解酶(ATGL)表达，减少胞内脂肪堆积[88]；下调肝组织固醇调节元件结合蛋白- 1C(SREBP- 1c)、和肝X受体表达，减少肝细胞脂肪生成[89]；上调糖尿病小鼠ATGL表达，减少内脏脂肪含量[90]。

高糖和亮氨酸通过AMPK/mTORC1/S6K1通路诱导大鼠骨骼肌胰岛素抵抗[91,92]。ALA增强骨骼肌细胞mTORC1上游抑制因子TSC2的磷酸化，同时激活AMPK改善胰岛素抵抗：增强骨骼肌细胞的胰岛素敏感性[93]；下调胰岛素β细胞S6K1表达，抑制分泌胰岛素[94]。

尽管在下丘脑细胞，ALA表现为抑制AMPK活性[95- 97]，但其结果是抑制食欲，协同ALA在外周组织激活AMPK活性改善胰岛素抵抗和减少脂肪生成、堆积，最终表现对治疗肥胖和糖尿病的益处。

综上所述，因疾病状态和靶细胞的不同，ALA对某些激酶活性的调节方向并不一致；但是，仍然提示ALA极有可能具有调节mTORC1信号通路的功能。因此，对于复发率高、疗效较差的自身免疫病患者来说，ALA在免疫细胞mTORC1信号通路中的调节作用更加值得进一步研究。

2.3中性粒细胞胞外诱捕网(Neutrophil extra- cellular traps，NETs) 中性粒细胞作为固有免疫系统重要成员，对病原体发挥重要的一线防御作用。除外吞噬和分泌炎症介质的防御方式，中性粒细胞还能释放NETs来捕获病原体。NETs是一种由核酸、组蛋白和颗粒蛋白组成的结构，它的形成过程伴或不伴有中性粒细胞的死亡，称之为NETosis[98]。研究表明NETs不仅能够抵御病原体的入侵，而且与某些自身免疫病的发病和血栓的形成有关[99]。NETs形成后在细胞外暴露多种自身抗原[100]，促进自身抗体的生成；NETs上调促炎因子、趋化因子和黏附分子的表达从而促进炎症反应；自身抗体延缓NETs降解，导致NETs持续存在，加剧炎症。NETs的形成过程必须依赖于ROS的生成和细胞自噬[101,102]，接受mTOR信号通路调节[103,104]；因此，可以推测ALA肯定的ROS清除能力和可能的mTOR信号通路调节功能将影响NETs的形成，进而减少自身抗原的形成，并且能够保护血管内皮。

2.4NLRP3炎症复合体 固有免疫细胞的NLRP3炎症复合体是一种多蛋白复合体，由NOD样受体3(NLRP3)、凋亡相关微粒蛋白(ASC)和半胱天冬酶- 1(caspase- 1)组成的，可活化caspase- 1，调控IL- 1β和IL- 18的加工和成熟，进而参与机体的固有免疫反应。线粒体源性的ROS是调控NLRP3炎性复合体活化的关键信号，线粒体外膜的电压依赖的阴离子通道(VDAC，是mPTP的组成部分)参与调节NLRP3活性[105]；线粒体受损积累产生过量ROS激活NLRP3炎症复合体[106]。NLRP3炎症复合体活化的IL- 1β上调炎症细胞Th17分化的关键性转录因子RORγt 和IRF4的表达[107,108]；Th17可分泌IL- 17和IL- 23，趋化中性粒细胞浸润炎症部位[109,110]，中性粒细胞的NLRP3炎症体进一步激活，加剧炎症，形成正反馈。多项研究表明NLRP3炎症复合体的激活与1型糖尿病[111]及某些自身免疫病发病相关。自身抗原U1核内小核糖核蛋白(U1- snRNP)在抗U1- snRNP抗体存在的情况下，激活人单核细胞内的NLRP3炎症复合体，刺激IL- 1β的分泌[112]。原发性干燥综合征患者唾液腺中NLRP3、ASC和caspase- 1表达上调，与患者唇腺活检的灶性指数(Focus score)呈正相关[113]。SLE患者NETs形成增多与巨噬细胞的NLRP3炎性复合体激活密切相关，两者组成正反馈网络，加剧炎症发生[114]；SLE患者内皮祖细胞功能失调与NLRP3炎症复合体激活相关[115]。因此，ALA可能通过调节线粒体功能和直接清除ROS这两个途径减少NLRP3炎症复合体激活，从而调节固有免疫细胞的功能。

2.5Nrf2信号通路 Nrf2是细胞抗氧化还原的中枢调节者。通过与ARE的相互作用，Nrf2可诱导编码抗氧化蛋白和Ⅱ型解毒酶的表达，在细胞的防御氧化应激保护中发挥重要作用[116]。有研究提示Nrf2缺陷小鼠会出现狼疮样改变[117]；Nrf2基因多态性与幼年起病的狼疮肾炎相关[118]；Nrf2(- /- )小鼠出现自身免疫性溶血性贫血[119]；此外，Nrf2缺陷可加重EAE病情[120]，而激活Nrf2信号通路则可改善EAE的神经系统炎症[121]。因此，作为Nrf2的激活剂[1]，ALA可以通过该信号通路发挥免疫调节功能。

3 ALA良好的安全性

ALA是人体的自然成分，作为药物在德国使用超过50年。在多项临床研究中， ALA每日口服剂量从600～2 400 mg不等，与安慰剂相比未发现副作用；或者静脉剂量600 mg/d连续使用3周没有发现严重不良反应[1,2]。Sen等[122]通过对比证实ALA促进Fas介导的Jurkat细胞凋亡，对健康人外周血淋巴细胞的凋亡却没有影响[122]。这一实验结果也提示ALA免疫调节的安全性。

综上所述，机体自然成分ALA不仅具有强大的抗氧化能力，而且可通过直接或间接的方式广泛地对固有免疫及适应性免疫系统进行调节。诸多实验结果提示ALA可能用于自身免疫疾病的治疗。目前免疫抑制剂是自身免疫性疾病治疗的主要手段，虽能在一定程度上缓解疾病，但较高的复发率及较大的药物副作用是临床面临的严峻问题。如果ALA的免疫调节作用能够获得进一步证实，那么对改善相关自身免疫性疾病的治疗效果意义重大，因此非常值得进一步研究。

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