梁湘輝，朱文浩，高 穎

(1. 山東省濟(jì)寧市中醫(yī)院，山東 濟(jì)寧 272013；2. 山東省淄博市中醫(yī)醫(yī)院，山東 淄博 255300；3. 北京中醫(yī)藥大學(xué)東直門醫(yī)院，北京 100700)

綜 述

小膠質(zhì)細(xì)胞介導(dǎo)多發(fā)性硬化發(fā)病的機(jī)制研究進(jìn)展

梁湘輝1，朱文浩2，高 穎3

(1. 山東省濟(jì)寧市中醫(yī)院，山東 濟(jì)寧 272013；2. 山東省淄博市中醫(yī)醫(yī)院，山東 淄博 255300；3. 北京中醫(yī)藥大學(xué)東直門醫(yī)院，北京 100700)

小膠質(zhì)細(xì)胞；多發(fā)性硬化；實(shí)驗(yàn)性自身免疫性腦脊髓炎；發(fā)病機(jī)制

多發(fā)性硬化(multiple sclerosis，MS)是一種自身免疫反應(yīng)引起的中樞神經(jīng)系統(tǒng)(central nervous system，CNS)慢性炎癥性脫髓鞘性疾病，以炎癥反應(yīng)、髓鞘脫失、軸突損傷、髓鞘再生和膠質(zhì)增生為主要病理特征[1]。MS的確切發(fā)病機(jī)制尚未完全闡明，但與自身免疫反應(yīng)有關(guān)。小膠質(zhì)細(xì)胞(microglial cell，MG)是CNS內(nèi)常駐免疫細(xì)胞，占所有膠質(zhì)細(xì)胞的10%～20%，靜息狀態(tài)下負(fù)責(zé)CNS的監(jiān)視作用，在大多數(shù)CNS病理?xiàng)l件下被激活，激活的MG發(fā)生形態(tài)學(xué)和分子學(xué)變化，參與先天和自適應(yīng)免疫反應(yīng)[2-3]。MS及實(shí)驗(yàn)性自身免疫性腦脊髓炎(experimental autoimmune encephalomyelitis，EAE)中均存在MG的激活。研究表明，MG的激活發(fā)生在脫髓鞘改變的2～4周前[4]。在MS和EAE中，MG不僅參與免疫反應(yīng)引起的CNS損傷，在疾病的恢復(fù)和神經(jīng)再生中也起重要作用[5]?，F(xiàn)對MG在MS和EAE中的作用進(jìn)行綜述。

1 抗原呈遞作用

MG是腦內(nèi)主要的抗原呈遞細(xì)胞(antigen-presenting cells，APCs)，參與了反應(yīng)性T細(xì)胞浸潤[6]。研究發(fā)現(xiàn)，在MS的急性活躍病灶和慢性活躍病灶的邊緣部存在大量的CD163+MG/巨噬細(xì)胞，慢性不活躍病灶和慢性活躍病灶的中央部罕見CD163+MG/巨噬細(xì)胞[7]。雙標(biāo)法顯示，在腦實(shí)質(zhì)和血管周圍CD163+MG/巨噬細(xì)胞內(nèi)堿性髓鞘蛋白(myelin basic protein，MBP)和人白細(xì)胞(位點(diǎn))DR抗原[human leukocyte antigen(locus)DR，HLA-DR]陽性，說明CD163+MG/巨噬細(xì)胞可以攝取和呈遞抗原[7]。MG(HLA-DR+細(xì)胞)的呈遞作用與MS病灶內(nèi)的軸突損傷密切相關(guān)，但軸突損傷部位的HLA-DR+細(xì)胞比髓鞘脫失處少[8]。在體外，原代人MG通過抗原呈遞作用可以降低人腦內(nèi)髓鞘和神經(jīng)元蛋白，引起髓鞘和神經(jīng)元損傷[8]。許多研究表明，神經(jīng)元抗原是自身免疫反應(yīng)的觸點(diǎn)[9-11]，因此攝取和呈遞神經(jīng)元抗原將加重病理性自身免疫反應(yīng)。MG可以攝取神經(jīng)元抗原，并將其呈遞給免疫反應(yīng)性T細(xì)胞，使其聚集到CNS并轉(zhuǎn)化成細(xì)胞毒性表型細(xì)胞(如Th1、Th17)，引起神經(jīng)損傷。

MG向T細(xì)胞進(jìn)行有效的抗原呈遞，需要能對抗原進(jìn)行識別、呈遞的主要組織相容性復(fù)合體(major histocompatibility complex，MHC)分子和APC中能與T細(xì)胞結(jié)合的協(xié)同刺激分子(co-stimulatory molecule)的共同參與。其中MHCⅡ吞噬呈遞抗原的作用受Toll樣受體(Toll-like receptor，TLR)和神經(jīng)元表達(dá)的膜糖蛋白CD200的調(diào)節(jié)[12-13]。MS中重要的T細(xì)胞協(xié)同刺激分子有CD40、CD137、B7糖蛋白等，它們通過與T細(xì)胞上的配體結(jié)合協(xié)同APC完成抗原呈遞作用[14-15]。

2 分泌白細(xì)胞介素(IL)

激活的MG可以釋放IL-1α、IL-1β、IL-2、IL-4、IL-6、IL-10、IL-12、IL-17、IL-18、IL-23、IL-27等[14，16]。IL-1β、IL-6、IL-12、IL-23可以使Th0細(xì)胞向Th1細(xì)胞和Th17細(xì)胞分化，二者均參與MS/EAE的發(fā)病。其中IL-12使Th0分化為Th1，進(jìn)而釋放IL-2、γ-干擾素(INF-γ)等，促進(jìn)T細(xì)胞增殖，加重炎癥反應(yīng)[17]。IL-1β、IL-6、IL-23可以使Th0分化為Th17，進(jìn)而釋放IL-6、IL-17、IL-23、腫瘤壞死因子-α(TNF-α)等，參與了EAE的發(fā)病。研究表明，MS患者復(fù)發(fā)時IL-17A、IL-6和IL-23p19均升高[18]，而MS或EAE的病情進(jìn)展與IL-23有密切關(guān)系。

IL-4主要由Th2細(xì)胞分泌，但激活的MG也可以釋放IL-4。IL-4是抗炎性細(xì)胞因子，能拮抗INF-γ產(chǎn)生的神經(jīng)破壞作用。Butovsky等[19]研究發(fā)現(xiàn)，IL-4可拮抗高濃度IFN-γ誘導(dǎo)的MG對少突膠質(zhì)細(xì)胞發(fā)生的阻礙作用。IL-4可以逆轉(zhuǎn)IFN-γ引起的抑制少突膠質(zhì)細(xì)胞發(fā)生的作用，減少TNF-α的生成，增加胰島素樣生長因子-1(IGF-1)的產(chǎn)生。在嚙齒類EAE的腦脊液中注射IL-4活化的MG，可以使脊髓中的少突膠質(zhì)細(xì)胞形成增加和臨床癥狀改善。IL-10可以與Th1效應(yīng)細(xì)胞上的IL-10受體結(jié)合，抑制炎癥性T細(xì)胞的轉(zhuǎn)移和增殖，對EAE起保護(hù)作用[20]。

3 分泌INF-γ

INF-γ是一種促炎性細(xì)胞因子，主要由Th1細(xì)胞分泌，但激活的MG也可以分泌INF-γ。激活的Th1細(xì)胞通過上調(diào)MHCⅡ分子和協(xié)同刺激分子B7-1和B7-2，使MG被激活并成為APCs?；罨腗G分泌IL-12、IL-18、IL-23和IL-27，使Th0細(xì)胞分化成Th1細(xì)胞，成熟的Th1 CD4+細(xì)胞又產(chǎn)生INF-γ，進(jìn)一步激活MG。同時，激活的MG也分泌INF-γ，形成正反饋回路[14]。INF-γ參與了炎癥反應(yīng)，促進(jìn)MS/EAE的發(fā)病。

近年來研究表明，INF-γ對MS/EAE也有保護(hù)作用，與誘導(dǎo)MG的凋亡有關(guān)。Takeuchi等[21]研究發(fā)現(xiàn)，INF-γ可以誘導(dǎo)MG的凋亡和活化MG誘導(dǎo)的細(xì)胞死亡，這可能是通過自限性負(fù)反饋調(diào)節(jié)實(shí)現(xiàn)的。MG的凋亡與促凋亡蛋白，特別是Bax的表達(dá)上調(diào)有關(guān)，而抑制凋亡蛋白的表達(dá)下調(diào)。INF-γ誘導(dǎo)的MG活化和后續(xù)死亡在MS的復(fù)發(fā)和緩解中起重要作用。

4 分泌TNF-α

TNF-α是一種促炎性細(xì)胞因子，在CNS主要由激活的MG分泌，通過抑制MG產(chǎn)生的TNF-α可以抑制炎癥性脫髓鞘。TNF-α可以中和抗體或結(jié)合重組的TNF受體蛋白，導(dǎo)致MS復(fù)發(fā)[14]。研究表明，TNF-α可以誘導(dǎo)MG釋放谷氨酸，引起神經(jīng)毒性損傷[22]。在體外，TNF-α可以下調(diào)少突膠質(zhì)細(xì)胞上的谷氨酸轉(zhuǎn)運(yùn)蛋白的表達(dá)、抑制谷氨酸的攝取和促進(jìn)NO的合成，加重MS/EAE的病情[14]。

此外，TNF還有神經(jīng)保護(hù)作用。在EAE中，TNF主要由T細(xì)胞和髓系細(xì)胞分泌，它可以協(xié)同抑制APCs產(chǎn)生IL-12p40和IL-6，進(jìn)而抑制致腦炎性T細(xì)胞發(fā)育成Th1和Th17，減輕EAE的病情[23]。

5 分泌胰島素樣生長因子(IGFs)

IGFs是CNS正常發(fā)育不可或缺的肽類激素，它能促進(jìn)少突膠質(zhì)細(xì)胞的發(fā)育、生存和髓磷脂合成，具有保護(hù)中樞神經(jīng)和生髓作用[24-25]。體內(nèi)和體外實(shí)驗(yàn)研究均表明，IGF-1能減少小鼠視網(wǎng)膜內(nèi)感光細(xì)胞的死亡，對營養(yǎng)不良的視網(wǎng)膜有神經(jīng)保護(hù)作用[26]。MG衍生的IGF-2能阻斷半乳糖腦苷脂(GalC)對少突膠質(zhì)細(xì)胞的毒性[27]。在缺氧缺血性腦病的損傷部位，MG表達(dá)IGF-1 mRNA[28]。胰島素樣生長因子-2(IGF-2)存在于未激活的和INF-γ處理的MG[24]。MG對神經(jīng)的保護(hù)作用是通過分泌IGF-1實(shí)現(xiàn)的[26]。其功能依賴于IGF結(jié)合蛋白高親和力調(diào)節(jié)因子(IGFBPs)，特別是IGFBP-2[24]。研究表明，MS的發(fā)病可能與IGF-1的生物利用度減少有關(guān)[29]，系統(tǒng)性注入IGF-1對EAE的臨床病程表現(xiàn)出多樣和瞬變的保護(hù)作用[30]。

6 分泌神經(jīng)生長因子(NGF)

NGF是第一個被發(fā)現(xiàn)的神經(jīng)營養(yǎng)因子，它能刺激外周和中樞神經(jīng)系統(tǒng)神經(jīng)元的分化、生存和生長，保護(hù)神經(jīng)元和髓鞘免受炎癥的損傷，調(diào)節(jié)免疫系統(tǒng)，減輕急性炎癥反應(yīng)過程中的興奮性毒性[31]。研究表明，激活的MG可以產(chǎn)生NGF，MG表達(dá)和釋放NGF受A2 a-腺苷受體的調(diào)節(jié)[32]。NGF與其高親和力的受體TrkA結(jié)合后發(fā)揮生物學(xué)作用。在EAE急性期，運(yùn)動神經(jīng)元中TrkA的免疫反應(yīng)減少，而在少突膠質(zhì)細(xì)胞中上調(diào)，并且主要集中在CNS白質(zhì)[33]，說明在EAE急性期神經(jīng)元損傷的同時，少突膠質(zhì)細(xì)胞被激活，發(fā)揮修復(fù)神經(jīng)元的作用。另有研究表明，在MS的損傷組織，神經(jīng)營養(yǎng)因子缺乏可以通過外周血單核細(xì)胞合成補(bǔ)償。在復(fù)發(fā)-緩解型MS，β-NGF與認(rèn)知表現(xiàn)密切相關(guān)，它在MS中可能起到神經(jīng)保護(hù)作用，特別是在認(rèn)知功能區(qū)[34]。

7 分泌趨化因子

在MS或EAE中，激活的MG高水平表達(dá)趨化因子(如CCL2～CCL5、CCL8、CCL19、CCL21、CXCL1和CXCL8～CXCL13等)及其受體(如CCR3、CXCR1和CXCR3等)[35]，募集白細(xì)胞、單核細(xì)胞、巨噬細(xì)胞、T細(xì)胞、B細(xì)胞和樹突狀細(xì)胞向CNS的病灶部位聚集，引起局部的神經(jīng)炎癥，參與髓鞘的吞噬[36]。對多種趨化因子受體敲除模型進(jìn)行研究表明，趨化因子對EAE的發(fā)病和進(jìn)展非常重要。如CCR1敲除小鼠表現(xiàn)出較輕的EAE，CCR2敲除小鼠表現(xiàn)出部分或完全抵抗EAE，CCR8敲除小鼠的病情減弱和臨床癥狀出現(xiàn)的時間延遲[14]。趨化因子還可以趨化抗炎性細(xì)胞，如CCL11募集Th2細(xì)胞到達(dá)MS病灶處，起到保護(hù)神經(jīng)的作用[37]。

8 分泌前列腺素(PGs)

PGs是花生四烯酸的衍生物，它可以調(diào)節(jié)多種生理系統(tǒng)，包括CNS、呼吸系統(tǒng)、心血管系統(tǒng)、胃腸系統(tǒng)、泌尿系統(tǒng)、內(nèi)分泌系統(tǒng)和免疫系統(tǒng)[38]。PGs是花生四烯酸通過環(huán)氧合酶1/2(COX1/2)通路合成的強(qiáng)效氧化脂質(zhì)分子，以自分泌和旁分泌的形式分泌[39-40]，與炎癥反應(yīng)有關(guān)，可能是MS病理變化的有效調(diào)節(jié)因子[38]。研究表明，在髓鞘脫失過程中腦內(nèi)的PGE2、PGD2和PGI2水平升高，在髓鞘再生過程中腦內(nèi)的PGE2、PGD2和PGI2水平恢復(fù)正常[41]。Kihara等[42]指出，EAE的病變主要與PGE2通路有關(guān)，而與PGD2、PGI2和5-脂氧合酶(5-LO)通路的關(guān)系較弱[42]。激活的MG可以通過COX-1/2合成和釋放PGE2，同時COX-PGE2通路受p38絲裂原活化蛋白激酶(p38MAPK)的調(diào)節(jié)[43]。PGE2合成和釋放受COX1/2的限制，因此調(diào)節(jié)MG內(nèi)COX-1/2的活性，可以調(diào)節(jié)PGE2的合成和釋放，從而影響EAE的病理變化和病情進(jìn)展。研究表明，阻斷COX1/2可以延遲EAE的發(fā)病，減輕EAE的病情，降低Th1型細(xì)胞因子的產(chǎn)生[40]。除促炎癥作用外，COX-2衍生的PGE2對先天免疫反應(yīng)還顯示出抗炎作用[44]，介導(dǎo)神經(jīng)保護(hù)。

9 分泌一氧化氮(NO)

NO是一種信號分子，也是一種神經(jīng)遞質(zhì)和自由基。正常條件下，它參與了血管擴(kuò)張、神經(jīng)功能和免疫反應(yīng)。此外，它還參與了許多病理反應(yīng)，如MS[45]。研究表明，NO及其衍生物在MS中發(fā)揮重要作用[46]；NO的代謝物增高與軸突變性和臨床殘疾相關(guān)[47]；在MS髓鞘脫失和髓鞘再生病變處表達(dá)誘導(dǎo)型一氧化氮合酶(iNOS)[48]。激活的MG可以表達(dá)iNOS mRNA及其蛋白，釋放NO。NO與超氧化物反應(yīng)產(chǎn)生過氧亞硝基(ONOO-)，對成熟少突膠質(zhì)細(xì)胞有毒性[49]。另有研究表明，內(nèi)皮型一氧化氮合酶缺陷(eNOS-/-)小鼠EAE的發(fā)病延遲，與血腦屏障(BBB)的破壞延遲有關(guān)。說明eNOS產(chǎn)生的NO是T細(xì)胞滲透至CNS的基礎(chǔ)。然而，eNOS-/- EAE小鼠的最終臨床癥狀更重，并且恢復(fù)延遲，說明NO在MS/EAE中有雙重作用，即促炎性作用和神經(jīng)保護(hù)作用[50]。

10 分泌谷氨酸

谷氨酸是哺乳動物大腦內(nèi)主要的興奮性神經(jīng)遞質(zhì)。經(jīng)谷氨酸突觸傳導(dǎo)的正常神經(jīng)沖動是整個大腦所需要的，是學(xué)習(xí)和記憶的基礎(chǔ)。然而，異常高水平的細(xì)胞外谷氨酸會導(dǎo)致神經(jīng)軸突細(xì)胞死亡[51]。研究表明，在MS脫髓鞘和軸突變性斑塊內(nèi)存在過量的谷氨酸釋放，最有可能釋放谷氨酸的細(xì)胞是浸潤的白細(xì)胞和激活的MG[52]。激活的MG通過谷氨酰胺酶生成谷氨酸，并經(jīng)縫隙連接的半通道釋放[53]。正常情況下，谷氨酸通過興奮性氨基酸轉(zhuǎn)運(yùn)蛋白(EAAT)轉(zhuǎn)運(yùn)。在MS中，激活的MG可以釋放ONOO-和氧自由基，下調(diào)EAAT的表達(dá)和功能，導(dǎo)致谷氨酸轉(zhuǎn)運(yùn)障礙，引起髓鞘、神經(jīng)元、突觸和少突膠質(zhì)細(xì)胞損傷。

11 分泌基質(zhì)金屬蛋白酶(MMPs)

MMPs屬于鋅依賴性肽鏈內(nèi)切酶，存在于中樞和外周神經(jīng)系統(tǒng)，參與了細(xì)胞外基質(zhì)和細(xì)胞基質(zhì)的重塑及相互反應(yīng)，與多種神經(jīng)病理性疾病有關(guān)，其中包括MS[54]。激活的MG可以分泌MMPs，MMPs在MS和EAE的MBP裂解和脫髓鞘中起重要作用[55]，并參與了神經(jīng)炎癥、血腦屏障(BBB)破壞和免疫反應(yīng)。

12 分泌活性氧(ROS)

研究表明，脂多糖(LPS)激活的BV-2小膠質(zhì)細(xì)胞產(chǎn)生ROS增加[56]，而激活的BV-2小膠質(zhì)細(xì)胞通過ROS通路使TNF-α和MCP-1增加[57]，參與MS和EAE的發(fā)病。

13 吞噬作用

在MS中，MG通過吞噬作用清除死亡細(xì)胞、誘導(dǎo)神經(jīng)營養(yǎng)因子、抗炎性細(xì)胞因子和抗氧化酶而顯示出神經(jīng)保護(hù)作用。

14 小結(jié)和展望

以上研究結(jié)果表明，MG在MS/EAE中的具體作用機(jī)制可能與以下幾方面作用有關(guān)：①抗原呈遞作用。MG可以將抗原呈遞給T細(xì)胞，使之分化成細(xì)胞毒性T細(xì)胞，參與免疫反應(yīng)。②吞噬作用。MG可以吞噬死亡的細(xì)胞或神經(jīng)元碎片，為神經(jīng)的修復(fù)提供有利環(huán)境，促進(jìn)神經(jīng)再生。③分泌各種細(xì)胞毒性物質(zhì)。如細(xì)胞因子、趨化因子、NO、谷氨酸、PGs、ROS等，在MS/EAE的過程中顯示出損害或保護(hù)兩方面的作用。

MG在MS/EAE的發(fā)病和修復(fù)中均起非常重要的作用，是治療MS的關(guān)鍵之一。因此，對MG在MS/EAE中的作用機(jī)制進(jìn)行系統(tǒng)而深入的研究，明確MG介導(dǎo)MS發(fā)病的可能機(jī)制，有助于從調(diào)節(jié)MG功能的角度而不是單純抑制MG功能的角度研發(fā)治療MS的新藥。

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朱文浩，E-mail：doctorzwh@163.com

國家自然科學(xué)基金資助項(xiàng)目(81072770)

10.3969/j.issn.1008-8849.2015.27.042

R364.32

A

1008-8849(2015)27-3067-05

2015-01-15