郭 娟 劉 瑋 李勝光

(解放軍總醫(yī)院第一附屬醫(yī)院風(fēng)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(dòng)植物體內(nèi)。在生理狀態(tài)下，人體內(nèi)的ALA作為線粒體丙酮酸脫氫酶和α- 酮戊二酸脫氫酶復(fù)合物的輔酶，保護(hù)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(duì)強(qiáng)力的氧化還原對(duì)。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(duì)機(jī)體的氧化損傷；還能參與體內(nèi)其他抗氧化劑的再生，因而被譽(yù)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(xì)胞內(nèi)外發(fā)揮抗氧化作用[1,2]。

基于其強(qiáng)有力的抗氧化功能和良好的安全性，ALA被廣泛應(yīng)用于糖尿病及其并發(fā)癥、神經(jīng)性疾病和心血管疾病。隨著相關(guān)研究的不斷深入，我們對(duì)ALA的作用機(jī)制有了更多的認(rèn)識(shí)，包括保護(hù)胰島細(xì)胞，增加胰島素敏感性，加快神經(jīng)傳導(dǎo)及改善血管內(nèi)皮功能[3]。除此之外，越來越多的實(shí)驗(yàn)數(shù)據(jù)提示ALA可能具有免疫調(diào)節(jié)作用。

近年來，氧化應(yīng)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(rèn)可。研究已證實(shí)ROS與免疫系統(tǒng)交互影響：一方面，ROS幾乎在每一種免疫細(xì)胞的信號(hào)傳導(dǎo)中發(fā)揮著生理作用。如巨噬細(xì)胞分泌ROS發(fā)揮抗菌作用；調(diào)節(jié)性T細(xì)胞(Treg)通過釋放ROS抑制其他T細(xì)胞的功能等[4]。另一方面，免疫細(xì)胞發(fā)生病理性改變時(shí)產(chǎn)生過量的ROS，加劇炎癥和免疫系統(tǒng)進(jìn)一步失衡。如氧化應(yīng)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(jìn)免疫紊亂的發(fā)生；而免疫紊亂則進(jìn)一步加劇氧化應(yīng)激水平，兩者共同參與了SLE的發(fā)生和發(fā)展。體外實(shí)驗(yàn)發(fā)現(xiàn)系統(tǒng)性硬化癥皮膚成纖維細(xì)胞硫辛酸及硫辛酸合成酶含量減低[6]，DHLA可逆轉(zhuǎn)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(chǔ)上，極可能發(fā)揮免疫調(diào)節(jié)作用。通過文獻(xiàn)復(fù)習(xí)，筆者對(duì)ALA的免疫調(diào)節(jié)的證據(jù)和可能機(jī)制進(jìn)行綜述。

1 ALA對(duì)免疫系統(tǒng)的調(diào)節(jié)功能

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

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

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

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

1.3固有免疫細(xì)胞(NK細(xì)胞、巨噬細(xì)胞和單核細(xì)胞) 天然殺傷細(xì)胞(NK cell)的功能主要由細(xì)胞毒作用和細(xì)胞因子的分泌組成：前者與溶酶體酶的釋放有關(guān)；后者以IFN- γ分泌為代表，IFN- γ是巨噬細(xì)胞的強(qiáng)力激活劑。ALA能夠抑制IL- 12/IL- 18介導(dǎo)的人NK細(xì)胞的IFN- γ分泌和細(xì)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(xì)胞內(nèi)cAMP的生成[21,22]℃AMP誘導(dǎo)生成的PGE2能夠抑制IL- 15介導(dǎo)的NK細(xì)胞的細(xì)胞毒性和IFN- γ分泌[23]。因此，ALA能夠從多個(gè)方面抑制NK細(xì)胞的功能。

研究者發(fā)現(xiàn)ALA通過直接和間接的方式調(diào)控巨噬細(xì)胞的活化、吞噬和遷移功能：ALA抑制EAE小鼠巨噬細(xì)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(nèi)臟脂肪組織的巨噬細(xì)胞浸潤和激活，抑制巨噬細(xì)胞分泌TNF- α和MCP- 1[25]，減輕內(nèi)臟脂肪組織炎癥。ALA通過Nrf2信號(hào)通路上調(diào)單核細(xì)胞的血紅色氧合酶- 1(HO- 1)表達(dá)，繼而抑制細(xì)胞因子的分泌[26]。還能夠通過抑制單核細(xì)胞的遷移功能并穩(wěn)定血腦屏障內(nèi)皮的功能而減輕EAE大鼠的中樞神經(jīng)炎癥細(xì)胞浸潤[9]。

2 ALA免疫調(diào)節(jié)的潛在靶點(diǎn)

ALA已經(jīng)廣泛運(yùn)用于臨床數(shù)十年，積累了大量的實(shí)驗(yàn)數(shù)據(jù)，根據(jù)相關(guān)的實(shí)驗(yàn)結(jié)果分析，筆者提出下列ALA免疫調(diào)節(jié)的潛在靶點(diǎn)。

2.1線粒體跨膜電位(mitochondrial membrane potential，ΔΨm) 線粒體是細(xì)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(xì)胞分化、調(diào)控細(xì)胞生長周期和細(xì)胞死亡。ΔΨm的穩(wěn)定有利于維持細(xì)胞的正常生理功能。電子傳遞鏈和ATP合酶維持的線粒體內(nèi)膜兩側(cè)的電化學(xué)梯度產(chǎn)生ΔΨm，因此ΔΨm、ATP和ROS三者的水平密切相關(guān)[27]。線粒體通透性轉(zhuǎn)變孔(mPTP)是位于線粒體內(nèi)外膜上的一組蛋白復(fù)合體，為非特異性通道，能維持ΔΨm及細(xì)胞內(nèi)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(dǎo)細(xì)胞凋亡或壞死[28]。生理狀態(tài)下，T細(xì)胞的激活或凋亡早期出現(xiàn)一過性可逆轉(zhuǎn)的ΔΨm升高即線粒體過級(jí)化(MHP)[29]；但SLE患者T細(xì)胞中MHP持續(xù)存在，導(dǎo)致ROS升高和ATP耗竭：一方面，MHP和ATP耗竭促進(jìn)T細(xì)胞壞死，繼而激活巨噬細(xì)胞和樹突狀細(xì)胞加劇炎癥[30]；另一方面，ROS水平升高促進(jìn)T細(xì)胞自發(fā)凋亡及IL- 10的釋放[31]。T細(xì)胞凋亡的增加導(dǎo)致自身抗原的釋放和疾病活動(dòng)；而IL- 10水平上升進(jìn)一步誘導(dǎo)T細(xì)胞凋亡并促進(jìn)B細(xì)胞過度活化[32- 35]。研究證明在一定的濃度范圍內(nèi)，ALA和DHLA促進(jìn)大鼠肝細(xì)胞線粒體mPTP開放[3,36]。因此，推測 ALA可能從多個(gè)方面改善SLE的線粒體功能失調(diào)，開放mPTP降低ΔΨm，改善SLE患者T細(xì)胞病理性的MHP；直接中和ROS，進(jìn)而糾正T、B細(xì)胞的功能失調(diào)。

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

在細(xì)胞質(zhì)中，mTORC1是許多信號(hào)級(jí)聯(lián)反應(yīng)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(yīng)激和Wnt等信號(hào)轉(zhuǎn)導(dǎo)通路通過多種途徑調(diào)控mTORC1活性：其中激酶Ras/Erk、PI3K/Akt和IKKβ為正向調(diào)控，而Dsh/GSK3和LKBl/AMPK為負(fù)向調(diào)控。mTORC1激活后抑制細(xì)胞自噬功能；通過磷酸化真核細(xì)胞翻譯起始因子4E結(jié)合蛋白1和核糖體S6蛋白激酶1促進(jìn)蛋白質(zhì)合成；通過活化轉(zhuǎn)錄因子固醇調(diào)節(jié)元件結(jié)合蛋白1(SREBP1)和過氧化物酶體增殖物激活受體γ(PPARγ)促進(jìn)脂質(zhì)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(diào)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(dú)發(fā)揮調(diào)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(hào)通路在免疫系統(tǒng)中發(fā)揮重要調(diào)節(jié)作用，影響大部分固有免疫細(xì)胞和適應(yīng)性免疫細(xì)胞的細(xì)胞發(fā)育和功能[41]。激活的mTORC1信號(hào)通路保證樹突狀細(xì)胞、巨噬細(xì)胞和中性粒細(xì)胞TLR的病原體識(shí)別功能；阻斷mTORC1信號(hào)通路損害固有免疫細(xì)胞功能，如樹突狀細(xì)胞的分化、抗原攝取、成熟和遷移，巨噬細(xì)胞的吞噬和趨化性，NK細(xì)胞的增殖和細(xì)胞毒性。在適應(yīng)性免疫應(yīng)答中，激活的mTORC1分子對(duì)于維持T細(xì)胞和B細(xì)胞的穩(wěn)定和活化意義重大，并促進(jìn)初始CD4+T細(xì)胞向Th1和Th17分化；抑制mTORC1活性則促進(jìn)初始CD4+T細(xì)胞向Treg分化[42,43]，也促使初始CD8+T細(xì)胞向記憶性CD8+T細(xì)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(hào)通路過度激活相關(guān)：1型糖尿病、MS、SLE和類風(fēng)濕關(guān)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(qiáng)其抑制功能有關(guān)[49,50]。SLE患者T細(xì)胞的mTORC1過度激活，阻斷CD4+CD25+T細(xì)胞的FOXP3表達(dá)，導(dǎo)致SLE患者Treg細(xì)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(xì)胞壞死和IL- 4分泌增加，IL- 4導(dǎo)致SLE患者CD25+CD19+B細(xì)胞(Breg)幾乎消失殆盡[52]，而Breg抑制CD4+效應(yīng)性T細(xì)胞增殖，上調(diào)Treg細(xì)胞FOXP3和CTLA- 4的表達(dá)[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(xì)胞基線和TCR激活后的胞內(nèi)鈣離子的水平[56]。但雷帕霉素不能改善SLE患者T細(xì)胞MHP狀態(tài)，反映了其對(duì)T細(xì)胞線粒體功能失調(diào)治療的局限性。IL- 22刺激RA患者的滑膜細(xì)胞增殖，與 PI3K/Akt/mTORC1信號(hào)通路激活相關(guān)[57]；抑制該通路減輕滑膜細(xì)胞的侵襲性[58]。在人TNF轉(zhuǎn)基因小鼠的關(guān)節(jié)炎中，mTORC1信號(hào)通路促進(jìn)滑膜破骨細(xì)胞的形成和活化，導(dǎo)致骨侵蝕和軟骨破壞；RA患者破骨細(xì)胞mTORC1信號(hào)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(yīng)用的障礙。

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

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

研究表明ALA阻斷Erk通路，改善動(dòng)脈粥樣硬化損傷并抑制血管平滑肌細(xì)胞增殖[64]；改善血管緊張素Ⅱ?qū)ρ芷交〖?xì)胞的氧化應(yīng)激損傷[65]；下調(diào)糖化血紅蛋白介導(dǎo)的小鼠巨噬細(xì)胞NF- κB和TGF- β1的表達(dá)[66]。ALA抑制小鼠系膜細(xì)胞5羥色胺(5- HT)和生長因子對(duì)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(dá)，并阻斷系膜細(xì)胞向肌成纖維細(xì)胞轉(zhuǎn)化[67，68]。ALA通過抑制Akt/S6K1和Erk活性減少促纖維化細(xì)胞因子(PDGF和TGF- β)對(duì)肝星狀細(xì)胞的激活和氧化應(yīng)激損傷，改善硫代乙酰胺誘導(dǎo)的大鼠肝硬化病情[69]。

ALA對(duì)于小鼠成纖維細(xì)胞的Erk1/2激酶具有雙向調(diào)節(jié)作用，取決于細(xì)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(duì)同一激酶出現(xiàn)不同調(diào)控方向。

ALA通過激活大鼠胰島素細(xì)胞的Akt激酶減少過氧化氫介導(dǎo)的細(xì)胞凋亡[72]。ALA可以通過激活A(yù)kt并抑制Erk，起到減少TNF- α和游離脂肪酸對(duì)大鼠骨骼肌細(xì)胞造成氧化應(yīng)激損傷[73]。近期臨床研究觀察到，2型糖尿病患者長期補(bǔ)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(xì)胞生長、促進(jìn)腫瘤細(xì)胞凋亡；誘導(dǎo)人肝癌細(xì)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(diào)小鼠脂肪細(xì)胞瘦素表達(dá)、抑制轉(zhuǎn)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A(yù)kt通路也介導(dǎo)多種細(xì)胞保護(hù)作用，如阻斷內(nèi)質(zhì)網(wǎng)應(yīng)激介導(dǎo)的大鼠甲狀腺細(xì)胞凋亡[79]，改善布比卡因、β- 淀粉樣肽和過氧化氫對(duì)大鼠神經(jīng)元的損害，改善缺血再灌注、TNF- α和游離脂肪酸對(duì)大鼠骨骼肌細(xì)胞造成氧化應(yīng)激等，改善過氧化氫介導(dǎo)的大鼠胰島素細(xì)胞凋亡，改善內(nèi)毒素血癥導(dǎo)致的心功能不全、血管內(nèi)皮功能不全，單核細(xì)胞活化和急性炎癥反應(yīng)[72,73,79- 84]。

2.2.2AMPK(負(fù)向調(diào)控mTORC1) ALA激活A(yù)MPK，上調(diào)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(diào)促纖維化細(xì)胞因子表達(dá)、減少膠原沉積改善糖尿病大鼠心肌病變[86]；促進(jìn)自發(fā)性高血壓大鼠血管舒張[87]；上調(diào)人肝細(xì)胞的脂肪組織甘油三酯水解酶(ATGL)表達(dá)，減少胞內(nèi)脂肪堆積[88]；下調(diào)肝組織固醇調(diào)節(jié)元件結(jié)合蛋白- 1C(SREBP- 1c)、和肝X受體表達(dá)，減少肝細(xì)胞脂肪生成[89]；上調(diào)糖尿病小鼠ATGL表達(dá)，減少內(nèi)臟脂肪含量[90]。

高糖和亮氨酸通過AMPK/mTORC1/S6K1通路誘導(dǎo)大鼠骨骼肌胰島素抵抗[91,92]。ALA增強(qiáng)骨骼肌細(xì)胞mTORC1上游抑制因子TSC2的磷酸化，同時(shí)激活A(yù)MPK改善胰島素抵抗：增強(qiáng)骨骼肌細(xì)胞的胰島素敏感性[93]；下調(diào)胰島素β細(xì)胞S6K1表達(dá)，抑制分泌胰島素[94]。

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

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

2.3中性粒細(xì)胞胞外誘捕網(wǎng)(Neutrophil extra- cellular traps，NETs) 中性粒細(xì)胞作為固有免疫系統(tǒng)重要成員，對(duì)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(zhì)的防御方式，中性粒細(xì)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(jié)構(gòu)，它的形成過程伴或不伴有中性粒細(xì)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(guān)[99]。NETs形成后在細(xì)胞外暴露多種自身抗原[100]，促進(jìn)自身抗體的生成；NETs上調(diào)促炎因子、趨化因子和黏附分子的表達(dá)從而促進(jìn)炎癥反應(yīng)；自身抗體延緩NETs降解，導(dǎo)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(xì)胞自噬[101,102]，接受mTOR信號(hào)通路調(diào)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(hào)通路調(diào)節(jié)功能將影響NETs的形成，進(jìn)而減少自身抗原的形成，并且能夠保護(hù)血管內(nèi)皮。

2.4NLRP3炎癥復(fù)合體 固有免疫細(xì)胞的NLRP3炎癥復(fù)合體是一種多蛋白復(fù)合體，由NOD樣受體3(NLRP3)、凋亡相關(guān)微粒蛋白(ASC)和半胱天冬酶- 1(caspase- 1)組成的，可活化caspase- 1，調(diào)控IL- 1β和IL- 18的加工和成熟，進(jìn)而參與機(jī)體的固有免疫反應(yīng)。線粒體源性的ROS是調(diào)控NLRP3炎性復(fù)合體活化的關(guān)鍵信號(hào)，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(diào)節(jié)NLRP3活性[105]；線粒體受損積累產(chǎn)生過量ROS激活NLRP3炎癥復(fù)合體[106]。NLRP3炎癥復(fù)合體活化的IL- 1β上調(diào)炎癥細(xì)胞Th17分化的關(guān)鍵性轉(zhuǎn)錄因子RORγt 和IRF4的表達(dá)[107,108]；Th17可分泌IL- 17和IL- 23，趨化中性粒細(xì)胞浸潤炎癥部位[109,110]，中性粒細(xì)胞的NLRP3炎癥體進(jìn)一步激活，加劇炎癥，形成正反饋。多項(xiàng)研究表明NLRP3炎癥復(fù)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(guān)。自身抗原U1核內(nèi)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(xì)胞內(nèi)的NLRP3炎癥復(fù)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(dá)上調(diào)，與患者唇腺活檢的灶性指數(shù)(Focus score)呈正相關(guān)[113]。SLE患者NETs形成增多與巨噬細(xì)胞的NLRP3炎性復(fù)合體激活密切相關(guān)，兩者組成正反饋網(wǎng)絡(luò)，加劇炎癥發(fā)生[114]；SLE患者內(nèi)皮祖細(xì)胞功能失調(diào)與NLRP3炎癥復(fù)合體激活相關(guān)[115]。因此，ALA可能通過調(diào)節(jié)線粒體功能和直接清除ROS這兩個(gè)途徑減少NLRP3炎癥復(fù)合體激活，從而調(diào)節(jié)固有免疫細(xì)胞的功能。

2.5Nrf2信號(hào)通路 Nrf2是細(xì)胞抗氧化還原的中樞調(diào)節(jié)者。通過與ARE的相互作用，Nrf2可誘導(dǎo)編碼抗氧化蛋白和Ⅱ型解毒酶的表達(dá)，在細(xì)胞的防御氧化應(yīng)激保護(hù)中發(fā)揮重要作用[116]。有研究提示Nrf2缺陷小鼠會(huì)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(guān)[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(hào)通路則可改善EAE的神經(jīng)系統(tǒng)炎癥[121]。因此，作為Nrf2的激活劑[1]，ALA可以通過該信號(hào)通路發(fā)揮免疫調(diào)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(xiàng)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(yán)重不良反應(yīng)[1,2]。Sen等[122]通過對(duì)比證實(shí)ALA促進(jìn)Fas介導(dǎo)的Jurkat細(xì)胞凋亡，對(duì)健康人外周血淋巴細(xì)胞的凋亡卻沒有影響[122]。這一實(shí)驗(yàn)結(jié)果也提示ALA免疫調(diào)節(jié)的安全性。

綜上所述，機(jī)體自然成分ALA不僅具有強(qiáng)大的抗氧化能力，而且可通過直接或間接的方式廣泛地對(duì)固有免疫及適應(yīng)性免疫系統(tǒng)進(jìn)行調(diào)節(jié)。諸多實(shí)驗(yàn)結(jié)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(fù)發(fā)率及較大的藥物副作用是臨床面臨的嚴(yán)峻問題。如果ALA的免疫調(diào)節(jié)作用能夠獲得進(jìn)一步證實(shí)，那么對(duì)改善相關(guān)自身免疫性疾病的治療效果意義重大，因此非常值得進(jìn)一步研究。

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