郭 娟 劉 瑋 李勝光

(解放軍總醫(yī)院第一附屬醫(yī)院風濕科，北京 100048)

α- 硫辛酸(α- Lipoic Acid，ALA)是由線粒體生成的二硫酚化合物，廣泛存在于動植物體內。在生理狀態(tài)下，人體內的ALA作為線粒體丙酮酸脫氫酶和α- 酮戊二酸脫氫酶復合物的輔酶，保護線粒體免受氧化攻擊。ALA是硫辛酸的氧化態(tài)，雙氫硫辛酸是硫辛酸的還原態(tài)，兩者組成一對強力的氧化還原對。它們能夠直接清除眾多活性氧自由基(Reactive oxygen species ，ROS)，作為金屬螯合劑減輕重金屬離子對機體的氧化損傷；還能參與體內其他抗氧化劑的再生，因而被譽為“萬能抗氧化劑”，且ALA及雙氫硫酸較好的水溶性和脂溶性使其在細胞內外發(fā)揮抗氧化作用[1,2]。

基于其強有力的抗氧化功能和良好的安全性，ALA被廣泛應用于糖尿病及其并發(fā)癥、神經性疾病和心血管疾病。隨著相關研究的不斷深入，我們對ALA的作用機制有了更多的認識，包括保護胰島細胞，增加胰島素敏感性，加快神經傳導及改善血管內皮功能[3]。除此之外，越來越多的實驗數(shù)據提示ALA可能具有免疫調節(jié)作用。

近年來，氧化應激在某些自身免疫疾病發(fā)生發(fā)展中的作用獲得普遍認可。研究已證實ROS與免疫系統(tǒng)交互影響：一方面，ROS幾乎在每一種免疫細胞的信號傳導中發(fā)揮著生理作用。如巨噬細胞分泌ROS發(fā)揮抗菌作用；調節(jié)性T細胞(Treg)通過釋放ROS抑制其他T細胞的功能等[4]。另一方面，免疫細胞發(fā)生病理性改變時產生過量的ROS，加劇炎癥和免疫系統(tǒng)進一步失衡。如氧化應激是系統(tǒng)性紅斑狼瘡(Systemic lupus erythematosus,SLE)普遍存在的病理狀態(tài)[5]，促進免疫紊亂的發(fā)生；而免疫紊亂則進一步加劇氧化應激水平，兩者共同參與了SLE的發(fā)生和發(fā)展。體外實驗發(fā)現(xiàn)系統(tǒng)性硬化癥皮膚成纖維細胞硫辛酸及硫辛酸合成酶含量減低[6]，DHLA可逆轉皮膚纖維化發(fā)生。由此可以推測，抗氧化劑可用于治療某些自身免疫性疾病，前者在清除ROS的基礎上，極可能發(fā)揮免疫調節(jié)作用。通過文獻復習，筆者對ALA的免疫調節(jié)的證據和可能機制進行綜述。

1 ALA對免疫系統(tǒng)的調節(jié)功能

1.1T細胞 多發(fā)性硬化(Multiple sclerosis，MS)是中樞神經系統(tǒng)(Central nervous system,CNS)的自身免疫病，以機體出現(xiàn)髓鞘特異性T細胞并通過血腦屏障進入CNS長期生存為特征。實驗性自身免疫性腦脊髓炎(EAE)是MS最常用的動物模型。多項研究發(fā)現(xiàn)使用ALA干預EAE建模過程，能夠減少病變部位炎癥細胞浸潤，減輕疾病的嚴重程度[7- 9]。最近，Wang等[8]證實ALA減少EAE病變組織的Th17和Th1細胞數(shù)量，增加脾臟Treg細胞數(shù)量，提示ALA對T細胞分化和增殖的免疫調節(jié)作用。另有實驗證實ALA上調高脂飲食小鼠空腸T細胞分化相關基因的表達，并使其恢復到正常水平(syk、CD86、CD28、CD2和CD25)，充分提示ALA參與調控T細胞的分化過程[10]。研究報道ALA能夠通過激活人外周血T細胞前列腺素受體EP2和EP4增加cAMP合成[11]，導致IL- 2及IL- 2Rα(CD25)表達的減少，繼而影響T細胞的增殖及激活[12]。

更多的研究提示ALA從多種途徑調節(jié)T細胞的功能：ALA能夠改善AIDS患者CD4+T細胞受損的線粒體功能[13]；下調人外周血T細胞表面CD4表達[14]；抑制CD4+T細胞分泌IFN- γ和IL- 4從而減輕特應性皮炎小鼠皮損的嚴重程度[15]。

除影響T細胞的增殖、分化和分泌功能，ALA還能夠抑制T細胞的遷移功能。Ying等[16]的研究發(fā)現(xiàn)在渡邊兔動脈粥樣硬化模型中，ALA干預后T細胞對趨化因子的反應下降，進而減少了動脈粥樣硬化斑塊中的T細胞浸潤。另有研究提示ALA抑制以下免疫細胞的遷移活動：EAE小鼠T細胞、EAE大鼠淋巴細胞和單核細胞、Jurkat細胞[9，17，18]。相關的機制研究提示遷移功能的抑制與ALA下調T細胞表面的極遲反應抗原4表達，并抑制微環(huán)境中的基質金屬蛋白酶9活性[18]。

1.2B細胞 高脂飲食小鼠表現(xiàn)為免疫細胞數(shù)量減少和功能下降?；虮磉_譜研究提示：(1)高脂飲食可下調小鼠空腸B細胞受體(B cell receptor,BCR)的信號通路基因(CD19、Cr2、Ighg和Igh- 6)的表達，ALA干預后這些基因明顯上調，其中Ighg甚至恢復正常水平[10]；(2)高脂飲食促進脾臟細胞凋亡，在ALA干預后獲明顯改善[19]。高脂飲食可同時減少外周血B細胞數(shù)量，ALA的治療作用可能與上調脾臟 BCR信號通路相關基因的表達水平(Fos、Akt3、Pi3k、Rac1、Igh- 6、Ighg)有關[20]。這一系列實驗證實ALA參與B細胞的增殖、凋亡及功能的調控。

1.3固有免疫細胞(NK細胞、巨噬細胞和單核細胞) 天然殺傷細胞(NK cell)的功能主要由細胞毒作用和細胞因子的分泌組成：前者與溶酶體酶的釋放有關；后者以IFN- γ分泌為代表，IFN- γ是巨噬細胞的強力激活劑。ALA能夠抑制IL- 12/IL- 18介導的人NK細胞的IFN- γ分泌和細胞毒性，通過依賴或者不依賴G蛋白偶聯(lián)受體(GPCRs)的方式增加細胞內cAMP的生成[21,22]℃AMP誘導生成的PGE2能夠抑制IL- 15介導的NK細胞的細胞毒性和IFN- γ分泌[23]。因此，ALA能夠從多個方面抑制NK細胞的功能。

研究者發(fā)現(xiàn)ALA通過直接和間接的方式調控巨噬細胞的活化、吞噬和遷移功能：ALA抑制EAE小鼠巨噬細胞吞噬髓磷脂[24]，減少自身抗原的遞呈；減少肥胖胰島素抵抗小鼠內臟脂肪組織的巨噬細胞浸潤和激活，抑制巨噬細胞分泌TNF- α和MCP- 1[25]，減輕內臟脂肪組織炎癥。ALA通過Nrf2信號通路上調單核細胞的血紅色氧合酶- 1(HO- 1)表達，繼而抑制細胞因子的分泌[26]。還能夠通過抑制單核細胞的遷移功能并穩(wěn)定血腦屏障內皮的功能而減輕EAE大鼠的中樞神經炎癥細胞浸潤[9]。

2 ALA免疫調節(jié)的潛在靶點

ALA已經廣泛運用于臨床數(shù)十年，積累了大量的實驗數(shù)據，根據相關的實驗結果分析，筆者提出下列ALA免疫調節(jié)的潛在靶點。

2.1線粒體跨膜電位(mitochondrial membrane potential，ΔΨm) 線粒體是細胞的能量站，為三羧酸循環(huán)和氧化磷酸化提供場所，并參與細胞分化、調控細胞生長周期和細胞死亡。ΔΨm的穩(wěn)定有利于維持細胞的正常生理功能。電子傳遞鏈和ATP合酶維持的線粒體內膜兩側的電化學梯度產生ΔΨm，因此ΔΨm、ATP和ROS三者的水平密切相關[27]。線粒體通透性轉變孔(mPTP)是位于線粒體內外膜上的一組蛋白復合體，為非特異性通道，能維持ΔΨm及細胞內外的離子平衡：mPTP過度開放，ΔΨm出現(xiàn)不可逆地降低直至耗盡，誘導細胞凋亡或壞死[28]。生理狀態(tài)下，T細胞的激活或凋亡早期出現(xiàn)一過性可逆轉的ΔΨm升高即線粒體過級化(MHP)[29]；但SLE患者T細胞中MHP持續(xù)存在，導致ROS升高和ATP耗竭：一方面，MHP和ATP耗竭促進T細胞壞死，繼而激活巨噬細胞和樹突狀細胞加劇炎癥[30]；另一方面，ROS水平升高促進T細胞自發(fā)凋亡及IL- 10的釋放[31]。T細胞凋亡的增加導致自身抗原的釋放和疾病活動；而IL- 10水平上升進一步誘導T細胞凋亡并促進B細胞過度活化[32- 35]。研究證明在一定的濃度范圍內，ALA和DHLA促進大鼠肝細胞線粒體mPTP開放[3,36]。因此，推測 ALA可能從多個方面改善SLE的線粒體功能失調，開放mPTP降低ΔΨm，改善SLE患者T細胞病理性的MHP；直接中和ROS，進而糾正T、B細胞的功能失調。

2.2哺乳動物雷帕霉素靶蛋白(mammalian target of rapamycin，mTOR)信號通路 mTOR是一種絲氨酸/蘇氨酸激酶，和不同蛋白質結合，可形成2種不同復合物，即mTOR復合物1(mTOR complex 1，mTORCl)和mTORC2。mTORC1廣泛存在于各種生物細胞，在調節(jié)細胞生長和代謝的過程中起到非常重要的作用[37]。

在細胞質中，mTORC1是許多信號級聯(lián)反應共同的中間環(huán)節(jié)，生長因子、ATP/ADP水平、血糖、氧含量、TNF- α、基因毒應激和Wnt等信號轉導通路通過多種途徑調控mTORC1活性：其中激酶Ras/Erk、PI3K/Akt和IKKβ為正向調控，而Dsh/GSK3和LKBl/AMPK為負向調控。mTORC1激活后抑制細胞自噬功能；通過磷酸化真核細胞翻譯起始因子4E結合蛋白1和核糖體S6蛋白激酶1促進蛋白質合成；通過活化轉錄因子固醇調節(jié)元件結合蛋白1(SREBP1)和過氧化物酶體增殖物激活受體γ(PPARγ)促進脂質合成；通過活化過氧化物酶體增殖物激活受體γ 輔助活化因子- 1α(PGC1- α)調控線粒體的氧化代謝和生物合成[38]。研究發(fā)現(xiàn)，位于線粒體外膜mTORC1與mPTP蛋白相連，通過感受ΔΨm的變化，單獨發(fā)揮調控線粒體代謝的功能；抑制mTORC1活性可以降低線粒體氧耗、ATP合成和ΔΨm[39，40]。

生理狀態(tài)下，mTORC1信號通路在免疫系統(tǒng)中發(fā)揮重要調節(jié)作用，影響大部分固有免疫細胞和適應性免疫細胞的細胞發(fā)育和功能[41]。激活的mTORC1信號通路保證樹突狀細胞、巨噬細胞和中性粒細胞TLR的病原體識別功能；阻斷mTORC1信號通路損害固有免疫細胞功能，如樹突狀細胞的分化、抗原攝取、成熟和遷移，巨噬細胞的吞噬和趨化性，NK細胞的增殖和細胞毒性。在適應性免疫應答中，激活的mTORC1分子對于維持T細胞和B細胞的穩(wěn)定和活化意義重大，并促進初始CD4+T細胞向Th1和Th17分化；抑制mTORC1活性則促進初始CD4+T細胞向Treg分化[42,43]，也促使初始CD8+T細胞向記憶性CD8+T細胞分化。

研究表明多種自身免疫病的發(fā)病可能與免疫系統(tǒng)的mTORC1信號通路過度激活相關：1型糖尿病、MS、SLE和類風濕關節(jié)炎(RA)[44- 48]。 mTORC1特異性抑制劑雷帕霉素改善1型糖尿病病情，與增加Treg數(shù)量并增強其抑制功能有關[49,50]。SLE患者T細胞的mTORC1過度激活，阻斷CD4+CD25+T細胞的FOXP3表達，導致SLE患者Treg細胞數(shù)量和功能的下降[51- 54]。mTORC1過度激活也引起CD3+CD4-CD8-T cells雙陰性T細胞壞死和IL- 4分泌增加，IL- 4導致SLE患者CD25+CD19+B細胞(Breg)幾乎消失殆盡[52]，而Breg抑制CD4+效應性T細胞增殖，上調Treg細胞FOXP3和CTLA- 4的表達[55]。雷帕霉素治療SLE初顯成效[5,47]，除改善上述異常外，它還降低SLE患者T細胞基線和TCR激活后的胞內鈣離子的水平[56]。但雷帕霉素不能改善SLE患者T細胞MHP狀態(tài)，反映了其對T細胞線粒體功能失調治療的局限性。IL- 22刺激RA患者的滑膜細胞增殖，與 PI3K/Akt/mTORC1信號通路激活相關[57]；抑制該通路減輕滑膜細胞的侵襲性[58]。在人TNF轉基因小鼠的關節(jié)炎中，mTORC1信號通路促進滑膜破骨細胞的形成和活化，導致骨侵蝕和軟骨破壞；RA患者破骨細胞mTORC1信號通路處于活化狀態(tài)[48]，mTORC1抑制劑聯(lián)合甲氨蝶呤治療能夠改善RA患者病情[59]。雖然雷帕霉素能夠特異抑制mTORC1改善上述自身免疫病病情，但是它與FK506相似的副作用可能成為臨床應用的障礙。

研究表明，ALA能夠在不同的病理狀態(tài)下，干預多種組織細胞mTORC1上游激酶的活性[1]。

2.2.1IKKβ、Ras/Erk1/2和PI3K/Akt和正向調控mTORC1 在RA患者成纖維樣滑膜細胞和人臍靜脈內皮細胞，ALA能夠阻斷TNF- α誘導IKKβ/NF- κB信號通路[60,61]。研究表明在腫瘤細胞和胰島素抵抗小鼠， TNF- α通過激活IKKβ正向調控mTORC1通路[62,63]。因此，推測ALA可能通過阻斷IKKβ激酶活性對mTORC1的活性產生負向調節(jié)作用。

研究表明ALA阻斷Erk通路，改善動脈粥樣硬化損傷并抑制血管平滑肌細胞增殖[64]；改善血管緊張素Ⅱ對血管平滑肌細胞的氧化應激損傷[65]；下調糖化血紅蛋白介導的小鼠巨噬細胞NF- κB和TGF- β1的表達[66]。ALA抑制小鼠系膜細胞5羥色胺(5- HT)和生長因子對Erk1/2的激活；減少腎小球腎炎小鼠腎臟促纖維因子TGF- β1表達，并阻斷系膜細胞向肌成纖維細胞轉化[67，68]。ALA通過抑制Akt/S6K1和Erk活性減少促纖維化細胞因子(PDGF和TGF- β)對肝星狀細胞的激活和氧化應激損傷，改善硫代乙酰胺誘導的大鼠肝硬化病情[69]。

ALA對于小鼠成纖維細胞的Erk1/2激酶具有雙向調節(jié)作用，取決于細胞培養(yǎng)液中是否含有血清[70,71]，這在一定程度上可以解釋ALA在不同的病理狀態(tài)下對同一激酶出現(xiàn)不同調控方向。

ALA通過激活大鼠胰島素細胞的Akt激酶減少過氧化氫介導的細胞凋亡[72]。ALA可以通過激活Akt并抑制Erk，起到減少TNF- α和游離脂肪酸對大鼠骨骼肌細胞造成氧化應激損傷[73]。近期臨床研究觀察到，2型糖尿病患者長期補充ALA可改善胰島素刺激的葡萄糖氧化和糖原合成，發(fā)揮降低胰島素水平及游離脂肪酸的作用[74]。

ALA抑制PI3K/Akt通路發(fā)揮抗腫瘤作用：抑制人乳腺癌細胞生長、促進腫瘤細胞凋亡；誘導人肝癌細胞凋亡[75，76]。ALA也通過抑制PI3K/Akt通路改善糖脂代謝失衡：下調小鼠脂肪細胞瘦素表達、抑制轉錄因子Sp1活性[77]；改善糖尿病大鼠的胰島素抵抗[78]。

然而，ALA激活Akt通路也介導多種細胞保護作用，如阻斷內質網應激介導的大鼠甲狀腺細胞凋亡[79]，改善布比卡因、β- 淀粉樣肽和過氧化氫對大鼠神經元的損害，改善缺血再灌注、TNF- α和游離脂肪酸對大鼠骨骼肌細胞造成氧化應激等，改善過氧化氫介導的大鼠胰島素細胞凋亡，改善內毒素血癥導致的心功能不全、血管內皮功能不全，單核細胞活化和急性炎癥反應[72,73,79- 84]。

2.2.2AMPK(負向調控mTORC1) ALA激活AMPK，上調白色脂肪組織分泌脂聯(lián)素改善高脂飲食大鼠的胰島素抵抗[85]；下調促纖維化細胞因子表達、減少膠原沉積改善糖尿病大鼠心肌病變[86]；促進自發(fā)性高血壓大鼠血管舒張[87]；上調人肝細胞的脂肪組織甘油三酯水解酶(ATGL)表達，減少胞內脂肪堆積[88]；下調肝組織固醇調節(jié)元件結合蛋白- 1C(SREBP- 1c)、和肝X受體表達，減少肝細胞脂肪生成[89]；上調糖尿病小鼠ATGL表達，減少內臟脂肪含量[90]。

高糖和亮氨酸通過AMPK/mTORC1/S6K1通路誘導大鼠骨骼肌胰島素抵抗[91,92]。ALA增強骨骼肌細胞mTORC1上游抑制因子TSC2的磷酸化，同時激活AMPK改善胰島素抵抗：增強骨骼肌細胞的胰島素敏感性[93]；下調胰島素β細胞S6K1表達，抑制分泌胰島素[94]。

盡管在下丘腦細胞，ALA表現(xiàn)為抑制AMPK活性[95- 97]，但其結果是抑制食欲，協(xié)同ALA在外周組織激活AMPK活性改善胰島素抵抗和減少脂肪生成、堆積，最終表現(xiàn)對治療肥胖和糖尿病的益處。

綜上所述，因疾病狀態(tài)和靶細胞的不同，ALA對某些激酶活性的調節(jié)方向并不一致；但是，仍然提示ALA極有可能具有調節(jié)mTORC1信號通路的功能。因此，對于復發(fā)率高、療效較差的自身免疫病患者來說，ALA在免疫細胞mTORC1信號通路中的調節(jié)作用更加值得進一步研究。

2.3中性粒細胞胞外誘捕網(Neutrophil extra- cellular traps，NETs) 中性粒細胞作為固有免疫系統(tǒng)重要成員，對病原體發(fā)揮重要的一線防御作用。除外吞噬和分泌炎癥介質的防御方式，中性粒細胞還能釋放NETs來捕獲病原體。NETs是一種由核酸、組蛋白和顆粒蛋白組成的結構，它的形成過程伴或不伴有中性粒細胞的死亡，稱之為NETosis[98]。研究表明NETs不僅能夠抵御病原體的入侵，而且與某些自身免疫病的發(fā)病和血栓的形成有關[99]。NETs形成后在細胞外暴露多種自身抗原[100]，促進自身抗體的生成；NETs上調促炎因子、趨化因子和黏附分子的表達從而促進炎癥反應；自身抗體延緩NETs降解，導致NETs持續(xù)存在，加劇炎癥。NETs的形成過程必須依賴于ROS的生成和細胞自噬[101,102]，接受mTOR信號通路調節(jié)[103,104]；因此，可以推測ALA肯定的ROS清除能力和可能的mTOR信號通路調節(jié)功能將影響NETs的形成，進而減少自身抗原的形成，并且能夠保護血管內皮。

2.4NLRP3炎癥復合體 固有免疫細胞的NLRP3炎癥復合體是一種多蛋白復合體，由NOD樣受體3(NLRP3)、凋亡相關微粒蛋白(ASC)和半胱天冬酶- 1(caspase- 1)組成的，可活化caspase- 1，調控IL- 1β和IL- 18的加工和成熟，進而參與機體的固有免疫反應。線粒體源性的ROS是調控NLRP3炎性復合體活化的關鍵信號，線粒體外膜的電壓依賴的陰離子通道(VDAC，是mPTP的組成部分)參與調節(jié)NLRP3活性[105]；線粒體受損積累產生過量ROS激活NLRP3炎癥復合體[106]。NLRP3炎癥復合體活化的IL- 1β上調炎癥細胞Th17分化的關鍵性轉錄因子RORγt 和IRF4的表達[107,108]；Th17可分泌IL- 17和IL- 23，趨化中性粒細胞浸潤炎癥部位[109,110]，中性粒細胞的NLRP3炎癥體進一步激活，加劇炎癥，形成正反饋。多項研究表明NLRP3炎癥復合體的激活與1型糖尿病[111]及某些自身免疫病發(fā)病相關。自身抗原U1核內小核糖核蛋白(U1- snRNP)在抗U1- snRNP抗體存在的情況下，激活人單核細胞內的NLRP3炎癥復合體，刺激IL- 1β的分泌[112]。原發(fā)性干燥綜合征患者唾液腺中NLRP3、ASC和caspase- 1表達上調，與患者唇腺活檢的灶性指數(shù)(Focus score)呈正相關[113]。SLE患者NETs形成增多與巨噬細胞的NLRP3炎性復合體激活密切相關，兩者組成正反饋網絡，加劇炎癥發(fā)生[114]；SLE患者內皮祖細胞功能失調與NLRP3炎癥復合體激活相關[115]。因此，ALA可能通過調節(jié)線粒體功能和直接清除ROS這兩個途徑減少NLRP3炎癥復合體激活，從而調節(jié)固有免疫細胞的功能。

2.5Nrf2信號通路 Nrf2是細胞抗氧化還原的中樞調節(jié)者。通過與ARE的相互作用，Nrf2可誘導編碼抗氧化蛋白和Ⅱ型解毒酶的表達，在細胞的防御氧化應激保護中發(fā)揮重要作用[116]。有研究提示Nrf2缺陷小鼠會出現(xiàn)狼瘡樣改變[117]；Nrf2基因多態(tài)性與幼年起病的狼瘡腎炎相關[118]；Nrf2(- /- )小鼠出現(xiàn)自身免疫性溶血性貧血[119]；此外，Nrf2缺陷可加重EAE病情[120]，而激活Nrf2信號通路則可改善EAE的神經系統(tǒng)炎癥[121]。因此，作為Nrf2的激活劑[1]，ALA可以通過該信號通路發(fā)揮免疫調節(jié)功能。

3 ALA良好的安全性

ALA是人體的自然成分，作為藥物在德國使用超過50年。在多項臨床研究中， ALA每日口服劑量從600～2 400 mg不等，與安慰劑相比未發(fā)現(xiàn)副作用；或者靜脈劑量600 mg/d連續(xù)使用3周沒有發(fā)現(xiàn)嚴重不良反應[1,2]。Sen等[122]通過對比證實ALA促進Fas介導的Jurkat細胞凋亡，對健康人外周血淋巴細胞的凋亡卻沒有影響[122]。這一實驗結果也提示ALA免疫調節(jié)的安全性。

綜上所述，機體自然成分ALA不僅具有強大的抗氧化能力，而且可通過直接或間接的方式廣泛地對固有免疫及適應性免疫系統(tǒng)進行調節(jié)。諸多實驗結果提示ALA可能用于自身免疫疾病的治療。目前免疫抑制劑是自身免疫性疾病治療的主要手段，雖能在一定程度上緩解疾病，但較高的復發(fā)率及較大的藥物副作用是臨床面臨的嚴峻問題。如果ALA的免疫調節(jié)作用能夠獲得進一步證實，那么對改善相關自身免疫性疾病的治療效果意義重大，因此非常值得進一步研究。

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