李海龍，畢曉瑩

血管性認(rèn)知障礙（vascular cognitive impairment，VCI）是目前人群中僅次于阿爾茨海默?。ˋlzheimer's disease，AD）導(dǎo)致癡呆的第二位疾病，隨著腦血管疾病發(fā)病率的不斷升高以及動(dòng)脈粥樣硬化、高血壓、糖尿病等血管性危險(xiǎn)因素在人群中愈發(fā)普遍，血管性認(rèn)知障礙所導(dǎo)致的癡呆已成為影響患者生存質(zhì)量的重要疾病[1]。目前血管性認(rèn)知障礙的發(fā)病機(jī)制不明，缺血低灌注、血腦屏障破壞、神經(jīng)營(yíng)養(yǎng)解偶聯(lián)等最終導(dǎo)致的以少突膠質(zhì)細(xì)胞死亡和髓鞘蛋白丟失為特征的腦白質(zhì)脫髓鞘病變被認(rèn)為是其重要的病理生理過程[1-2]。病理學(xué)研究顯示，損傷腦白質(zhì)中的氧化應(yīng)激和炎癥反應(yīng)標(biāo)記物（如細(xì)胞因子和黏附分子）的水平與血管性認(rèn)知障礙相關(guān)[3-5]。與此同時(shí)，損傷區(qū)域還出現(xiàn)了小膠質(zhì)細(xì)胞（microglia）的激活和反應(yīng)性的星形膠質(zhì)細(xì)胞（reactive astrocytes，RAs），且伴有外周血中上述標(biāo)記物的上升[6-9]。因此，血管性認(rèn)知障礙的炎癥假說認(rèn)為這種缺血缺血氧環(huán)境下的小膠質(zhì)細(xì)胞過度激活介導(dǎo)的炎癥反應(yīng)可破壞血腦屏障，并造成腦白質(zhì)的損傷（white matter lesions，WMLs），促進(jìn)血管性認(rèn)知障礙的發(fā)生發(fā)展。本文就缺氧誘導(dǎo)小膠質(zhì)細(xì)胞激活進(jìn)而介導(dǎo)非特異性炎癥反應(yīng)導(dǎo)致白質(zhì)脫髓鞘損傷的機(jī)制研究做一綜述。

1 缺血缺氧條件下CX3趨化因子受體-配體信號(hào)對(duì)小膠質(zhì)細(xì)胞激活的調(diào)節(jié)作用

小膠質(zhì)細(xì)胞是中樞神經(jīng)系統(tǒng)中的固有免疫細(xì)胞，對(duì)病原體和組織損傷起首要的反應(yīng)。激活的小膠質(zhì)細(xì)胞可產(chǎn)生大量的有助于清除病原感染和壞死組織的促炎介質(zhì)，包括細(xì)胞因子、趨化因子、活性氧簇（reactive oxygen species，ROS）和一氧化氮。然而長(zhǎng)期過度的小膠質(zhì)細(xì)胞激活可導(dǎo)致病理性炎癥觸發(fā)神經(jīng)毒性反應(yīng)進(jìn)而引起神經(jīng)退行性疾病或腫瘤形成[10-11]。同時(shí)這種過度活化狀態(tài)的小膠質(zhì)細(xì)胞也是腦內(nèi)腫瘤壞死因子（tumor necrosis factor，TNF）α、白細(xì)胞介素（interleukin，IL）-1β、IL-6等具有神經(jīng)毒性的促炎因子的主要來源[12]。因此，小膠質(zhì)細(xì)胞的過度激活是血管性認(rèn)知障礙中慢性持續(xù)炎癥反應(yīng)啟動(dòng)的關(guān)鍵環(huán)節(jié)。

在正常腦內(nèi)，小膠質(zhì)細(xì)胞正常活化狀態(tài)的維持依賴于神經(jīng)元持續(xù)地表達(dá)一種CX3趨化因子配體1（CX3 chemokine ligand1，CX3CL1）作用于小膠質(zhì)細(xì)胞上的特有CX3趨化因子受體（CX3 chemokine receptors，CX3CR1）[13-14]。有研究在短暫大腦中動(dòng)脈阻斷（middle cerebral artery occlusion，MCAO）動(dòng)物模型中發(fā)現(xiàn)，CX3CR1敲除的小鼠腦梗死區(qū)面積及血腦屏障破壞程度均輕于對(duì)照組，且IL-1β和TNF-α信使核糖核酸（messenger ribonucleic acid，mRNA）的表達(dá)均低于對(duì)照組[15]。這與Cardona[16]與Corona等[17]發(fā)現(xiàn)在給予細(xì)菌脂多糖（lipopolysaccharides，LPS）注射的CX3CR1敲除小鼠腦組織中IL-1β表達(dá)較未敲除的對(duì)照組明顯升高的結(jié)果并不一致。另一項(xiàng)研究發(fā)現(xiàn)，在MCAO小鼠模型中，與對(duì)照組相比，CX3CR1缺失的小鼠除了梗死面積減少外，還展現(xiàn)出較少的神經(jīng)元凋亡和活性氧水平，同時(shí)小膠質(zhì)細(xì)胞更多表現(xiàn)為可替代激活狀態(tài)（M2型）且伴有TNF-α、IL-1β、IL-6表達(dá)的明顯下降[18]。因此，在缺血缺氧環(huán)境下，CX3CR1信號(hào)缺失可能通過促進(jìn)小膠質(zhì)細(xì)胞可替代激活狀態(tài)（M2型）表達(dá)來抑制小膠質(zhì)細(xì)胞經(jīng)典激活狀態(tài)（M1型）從而發(fā)揮神經(jīng)保護(hù)作用，這對(duì)減緩小膠質(zhì)細(xì)胞過度激活對(duì)神經(jīng)元或少突膠質(zhì)細(xì)胞造成的損害可能具有重要意義。

在血管性認(rèn)知障礙中，慢性腦缺血被認(rèn)為是導(dǎo)致WMLs的主要病因。一些研究報(bào)道，激活的小膠質(zhì)細(xì)胞在WMLs的病理生理過程中十分關(guān)鍵[19-20]。劉勇等在體外實(shí)驗(yàn)中的研究發(fā)現(xiàn)，通過構(gòu)建針對(duì)CX3CR1的短發(fā)夾核糖核酸（short hairpin ribonucleic acid，shRNA）并轉(zhuǎn)導(dǎo)低氧條件下培養(yǎng)的小膠質(zhì)細(xì)胞，可使低氧誘導(dǎo)的小膠質(zhì)細(xì)胞增殖減緩，且細(xì)胞因子TNF-α和IL-1β表達(dá)下降，同時(shí)伴有絲裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）與蛋白激酶C（protein kinase C，PKC）總蛋白的表達(dá)下降，提示p38MAPK/PKC通路的激活可能參與了缺氧所介導(dǎo)的小膠質(zhì)細(xì)胞激活和炎癥因子釋放[21]。這與在體實(shí)驗(yàn)中，CX3CR1敲除的MCAO模型小鼠病變側(cè)腦內(nèi)上述炎性細(xì)胞因子的表達(dá)下降結(jié)果一致，但不同于LPS誘導(dǎo)小膠質(zhì)細(xì)胞激活模型中CX3CR1敲除后IL-1β表達(dá)升高。這提示CX3CR1信號(hào)缺失對(duì)機(jī)體在受外界刺激后炎癥因子水平的影響并不一致，這可能與小膠質(zhì)細(xì)胞激活的啟動(dòng)因素不同有關(guān)，特別是在不同的病理?xiàng)l件下，CX3CL1-CX3CR1信號(hào)對(duì)小膠質(zhì)細(xì)胞的調(diào)節(jié)作用可能有所不同，但其作用機(jī)制目前仍不十分清楚。有學(xué)者猜測(cè)，CX3CL1的膜結(jié)合形式是維持小膠質(zhì)細(xì)胞靜息狀態(tài)的主要分子，可抑制IL-1β和TNF-α的釋放，而可溶解形式CX3CL1與CX3CR1結(jié)合可激活小膠質(zhì)細(xì)胞釋放以IL-1β為主的炎性細(xì)胞因子[22]。

2 TOLL樣受體4在缺血缺氧條件下小膠質(zhì)細(xì)胞介導(dǎo)的炎癥反應(yīng)中的作用

TOLL樣受體4（Toll-like receptor 4，TLR 4）主要表達(dá)于小膠質(zhì)細(xì)胞，可被多種內(nèi)源性或外源性因子所激活，通過進(jìn)一步激活下游的信號(hào)通路，參與小膠質(zhì)細(xì)胞介導(dǎo)的神經(jīng)炎癥反應(yīng)[23]。目前的研究已發(fā)現(xiàn)TLR4依賴的小膠質(zhì)細(xì)胞激活參與了多種神經(jīng)免疫疾病及退行性疾病的慢性炎癥過程[24-25]。此外，近年來的研究發(fā)現(xiàn)TLR4所介導(dǎo)的炎癥反應(yīng)還參與了腦缺血性疾病的發(fā)生。Caso等[26-27]首次對(duì)TLR4在永久MCAO小鼠模型中的作用進(jìn)行了研究，結(jié)果發(fā)現(xiàn)TLR4敲除的小鼠在缺血?jiǎng)?chuàng)傷后IL-1β水平降低，同時(shí)伴有梗死區(qū)面積減小及反映血腦屏障破壞程度的基質(zhì)金屬蛋白酶（matrix metalloproteinase-9，MMP-9）表達(dá)減少。體外研究中同樣發(fā)現(xiàn)，缺氧可使小膠質(zhì)細(xì)胞TLR4表達(dá)升高[28]。這說明TLR4信號(hào)參與了缺血性炎癥反應(yīng)及其造成的腦組織破壞。此外，有研究在脊髓缺血再灌注損傷的模型中發(fā)現(xiàn)，TLR4敲除可減緩脊髓中小膠質(zhì)細(xì)胞的活化程度及炎癥因子的釋放[29]。在術(shù)后認(rèn)知障礙的研究中發(fā)現(xiàn)，隨著TLR4和炎癥因子表達(dá)水平恢復(fù)正常，認(rèn)知功能隨之改善[30]。因此，缺血條件下TLR4高表達(dá)對(duì)小膠質(zhì)細(xì)胞的活化同樣具有一定的調(diào)節(jié)作用，且可能損害認(rèn)知功能，但尚缺乏慢性缺血低灌注狀態(tài)下的研究。

目前缺血缺氧導(dǎo)致小膠質(zhì)細(xì)胞TLR4高表達(dá)及其激活下游炎性信號(hào)通路的機(jī)制尚不十分清楚。其中缺血缺氧所介導(dǎo)的熱休克蛋白60（heat shock proteins，HSP60）和高遷移率蛋白-1（high-mobility group box 1，HMGB1）被認(rèn)為是缺血缺氧下與TLR4相結(jié)合而參與炎癥反應(yīng)的潛在內(nèi)源性配體[31-32]。TLR4所介導(dǎo)的信號(hào)主要通過髓樣分化因子88（myeloid differentiation factor 88，MyD88）和干擾素TIR結(jié)構(gòu)域銜接蛋白（Toll/interleukin-1receptor-domain-containing adaptorinducing interferon-β，TRIF）兩個(gè)通路進(jìn)行傳遞。體外研究發(fā)現(xiàn)，在小膠質(zhì)細(xì)胞中，低氧可使LPS介導(dǎo)的干擾素調(diào)節(jié)因子3（interferon regulatory factor-3，IRF-3）的激活及隨后β干擾素的表達(dá)增強(qiáng)，但同時(shí)抑制LPS通過MyD88通路激活核轉(zhuǎn)錄因子kappa B（nucleartranscriptionfactor kappa B，NF-κB）[28]。提示低氧對(duì)TLR4下游的信號(hào)通路調(diào)節(jié)可能與其他刺激有所不同。而在缺血預(yù)適應(yīng)對(duì)腦缺血性損傷的保護(hù)機(jī)制研究中發(fā)現(xiàn)，大鼠經(jīng)短暫的缺血預(yù)適應(yīng)后，TRIF/IRF-3表達(dá)水平升高，盡管NF-κB的表達(dá)同時(shí)升高，但其在細(xì)胞質(zhì)中始終維持著一種不活躍狀態(tài)[33]。因此，在缺血缺氧條件下TLR4下游信號(hào)通路的表達(dá)變化可能是小膠質(zhì)細(xì)胞所介導(dǎo)的炎癥反應(yīng)強(qiáng)弱的關(guān)鍵，其中TRIF信號(hào)通路對(duì)炎癥介導(dǎo)的缺血性損傷具有一定的保護(hù)作用。鑒于在血管性認(rèn)知障礙中炎癥因子水平與認(rèn)知損害密切相關(guān)，通過調(diào)節(jié)TLR4下游信號(hào)的表達(dá)可能在抑制血管性認(rèn)知障礙發(fā)生發(fā)展中具有重要作用。

3 小膠質(zhì)細(xì)胞激活對(duì)少突膠質(zhì)細(xì)胞的炎性損傷作用

近些年來的研究發(fā)現(xiàn)，由靜息狀態(tài)激活后的小膠質(zhì)細(xì)胞可表現(xiàn)為兩種不同活化狀態(tài)：經(jīng)典激活狀態(tài)（M1型）和選擇性激活狀態(tài)（M2型）。M2型小膠質(zhì)細(xì)胞通過產(chǎn)生抗炎細(xì)胞因子及神經(jīng)營(yíng)養(yǎng)因子發(fā)揮神經(jīng)保護(hù)作用促進(jìn)內(nèi)穩(wěn)態(tài)的恢復(fù)，而在外界損傷刺激下，小膠質(zhì)細(xì)胞激活常表現(xiàn)為M1型進(jìn)而釋放大量的炎性細(xì)胞因子及ROS，而過度釋放的TNF-α還可作用于小膠質(zhì)細(xì)胞上的TNF-R1促使其持續(xù)激活介導(dǎo)慢性炎癥的發(fā)生[34]。臨床研究發(fā)現(xiàn)，伴有小膠質(zhì)細(xì)胞活化標(biāo)記物YKL-40和sCD14持續(xù)升高的輕度認(rèn)知損害患者更易發(fā)展為血管性癡呆（vascular dementia，VaD）[35]。因而小膠質(zhì)細(xì)胞的持續(xù)活化是促進(jìn)血管性認(rèn)知障礙發(fā)生發(fā)展的重要因素。

以少突膠質(zhì)細(xì)胞死亡為主的髓鞘脫失及再生障礙是血管性認(rèn)知障礙進(jìn)行性發(fā)展的重要病理學(xué)特征。在腦血管疾病及多種血管性危險(xiǎn)因素造成的缺血缺氧條件下，小膠質(zhì)細(xì)胞可被激活為M1狀態(tài)，進(jìn)而釋放大量炎癥因子對(duì)少突膠質(zhì)細(xì)胞及神經(jīng)元的軸突造成損害。過度釋放的TNF-α和IL-1β作為主要炎癥因子可進(jìn)一步作用于神經(jīng)元或少突膠質(zhì)細(xì)胞上的相應(yīng)受體產(chǎn)生炎性損傷作用。TNF-α激活其受體TNF-R1可通過半胱天冬酶信號(hào)通路誘導(dǎo)細(xì)胞凋亡[36]。在初生小鼠中，當(dāng)暴露于低氧環(huán)境時(shí)，腦室周圍白質(zhì)少突膠質(zhì)細(xì)胞上的TNF-R1表達(dá)增多，TNF-α可與之結(jié)合加強(qiáng)其介導(dǎo)少突膠質(zhì)細(xì)胞的凋亡[19]。體外研究還發(fā)現(xiàn)，來自TNF-R1/TNFR2敲除的小鼠中獲得的少突膠質(zhì)細(xì)胞祖細(xì)胞能夠抵抗由LPS介導(dǎo)的小膠質(zhì)細(xì)胞毒性作用[37]。IL-1R1在低氧時(shí)也有表達(dá)升高，IL-1β與之結(jié)合后盡管并不引起細(xì)胞凋亡，但過度表達(dá)的IL-1β可通過與神經(jīng)干細(xì)胞上的IL-1R1結(jié)合激活NF-κB信號(hào)可抑制海馬的神經(jīng)再生循環(huán)，甚至導(dǎo)致動(dòng)物的抑郁行為[38]。因此，低氧條件下TNF-R1在少突膠質(zhì)細(xì)胞上的過度表達(dá)從而介導(dǎo)TNF-α所引起的少突膠質(zhì)細(xì)胞凋亡以及IL-1β作用于神經(jīng)干細(xì)胞所導(dǎo)致的神經(jīng)再生障礙可能是血管性認(rèn)知障礙WMLs發(fā)生的重要機(jī)制。與M1型小膠質(zhì)細(xì)胞不同的是，M2型小膠質(zhì)細(xì)胞對(duì)腦白質(zhì)脫髓鞘損傷中少突膠質(zhì)細(xì)胞的分化具有驅(qū)動(dòng)作用，且為髓鞘再生所必需，其釋放的活化素A（activin-A）促進(jìn)少突膠質(zhì)細(xì)胞前體細(xì)胞（oligodendrocyte precursor cells，OPCs）向少突膠質(zhì)細(xì)胞的分化[39]。由此可見，適當(dāng)?shù)卣{(diào)節(jié)小膠質(zhì)細(xì)胞的活化狀態(tài)可能有助于減少缺血缺氧條件下的少突膠質(zhì)細(xì)胞損傷并促進(jìn)髓鞘再生修復(fù)。

4 炎癥因子與多種神經(jīng)營(yíng)養(yǎng)因子在少突膠質(zhì)細(xì)胞前體細(xì)胞分化成熟中的相互作用

近些年的研究發(fā)現(xiàn)，慢性缺血缺氧所導(dǎo)致的腦白質(zhì)損傷主要是由于OPCs的成熟終止以致不能夠正常分化為少突膠質(zhì)細(xì)胞進(jìn)而形成髓鞘，且可能是血管性癡呆中腦白質(zhì)脫髓鞘損傷后髓鞘再生障礙的重要原因[40-41]。腦內(nèi)多種細(xì)胞源性的神經(jīng)營(yíng)養(yǎng)因子對(duì)OPCs向少突膠質(zhì)細(xì)胞的分化成熟修復(fù)髓鞘具有促進(jìn)作用[42-44]。因此，在缺血缺氧微環(huán)境下，改善低水平的神經(jīng)營(yíng)養(yǎng)因子表達(dá)可能有助于修復(fù)血管性認(rèn)知障礙損傷的白質(zhì)。

腦內(nèi)神經(jīng)營(yíng)養(yǎng)因子種類和來源十分復(fù)雜，其中神經(jīng)膠質(zhì)細(xì)胞是其主要來源，其神經(jīng)保護(hù)及修復(fù)髓鞘的作用與抑制炎癥因子的促凋亡作用密切相關(guān)。Wang Y等[45]在缺血缺氧腦損傷模型中發(fā)現(xiàn)，神經(jīng)生長(zhǎng)因子（nerve growth factor，NGF）和腦源性神經(jīng)生長(zhǎng)因子（brainderived neurotrophic factor，BDNF）表達(dá)水平顯著降低，同時(shí)伴TNF-α和IL-1β的表達(dá)增高。這提示小膠質(zhì)細(xì)胞激活釋放的炎性細(xì)胞因子與神經(jīng)營(yíng)養(yǎng)因子對(duì)缺血性損傷起相反的調(diào)節(jié)作用。大量釋放的TNF-α可與少突膠質(zhì)細(xì)胞及OPCs上的TNFR1結(jié)合造成細(xì)胞損傷，而與TNFR2結(jié)合則具有神經(jīng)保護(hù)作用。體外研究發(fā)現(xiàn)，TNF-α作用于TNFR2后可激活磷脂酰肌醇3激酶-蛋白激酶B/Akt通路介導(dǎo)星形膠質(zhì)細(xì)胞源性的白血病抑制因子（leukemia inhibitory factor，LIF）產(chǎn)生，從而促進(jìn)共培養(yǎng)的OPCs分化為髓鞘堿性蛋白表達(dá)陽性的成熟少突膠質(zhì)細(xì)胞[42]。與TNFR2作用相似的是，胰島素樣生長(zhǎng)因子1（insulin-like growth factor-1，IGF-1）也可通過激活磷脂酰肌醇3激酶-蛋白激酶B/Akt通路進(jìn)而阻斷TNF-α誘導(dǎo)的線粒體凋亡來保護(hù)OPCs從而促進(jìn)其分化[46]。此外，盡管小膠質(zhì)細(xì)胞被認(rèn)為是導(dǎo)致缺血后腦組織炎性損傷的主要細(xì)胞，但在短暫腦缺血后恢復(fù)靜息狀態(tài)小膠質(zhì)細(xì)胞可通過釋放IGF-1發(fā)揮神經(jīng)保護(hù)作用[47]。IL-1β敲除的小鼠可伴有小膠質(zhì)細(xì)胞和星形膠質(zhì)細(xì)胞生成IGF-1減少以至其腦內(nèi)急性脫髓鞘損傷后少突膠質(zhì)細(xì)胞成熟障礙[48]。因此，在缺血后炎癥反應(yīng)中，炎癥因子除了對(duì)組織造成損害外，還具有一定介導(dǎo)神經(jīng)營(yíng)養(yǎng)因子表達(dá)促進(jìn)OPCs及少突膠質(zhì)細(xì)胞分化成熟的作用，同時(shí)神經(jīng)營(yíng)養(yǎng)因子對(duì)抗炎癥因子所誘導(dǎo)的凋亡具有神經(jīng)保護(hù)作用，這一系列相互的調(diào)節(jié)作用在促進(jìn)神經(jīng)元再生及髓鞘修復(fù)中有望成為有效的治療策略。

5 總結(jié)

近年來，炎性機(jī)制在癡呆的發(fā)病機(jī)制中的作用越來越受到重視。與AD病理中Aβ沉積誘導(dǎo)的慢性炎癥致神經(jīng)元變性不同的是，在血管性認(rèn)知障礙中，其慢性炎癥反應(yīng)常由多種血管性危險(xiǎn)因素導(dǎo)致的缺血缺氧所引起，且病理改變多以腦室旁深部白質(zhì)病變?yōu)樘卣鳌Ｐ∧z質(zhì)細(xì)胞作為中樞神經(jīng)系統(tǒng)中起免疫監(jiān)視的主要細(xì)胞，其在慢性缺血缺氧條件下的持續(xù)激活必然是血管性認(rèn)知障礙發(fā)生發(fā)展的關(guān)鍵環(huán)節(jié)。小膠質(zhì)細(xì)胞激活所釋放的多種細(xì)胞因子能夠通過與相應(yīng)受體結(jié)合從而產(chǎn)生多種形式的生物學(xué)效應(yīng)，參與少突膠質(zhì)細(xì)胞的凋亡及髓鞘的脫失。這一病理生理過程的調(diào)控十分復(fù)雜，本文僅對(duì)小膠質(zhì)細(xì)胞激活介導(dǎo)的炎癥反應(yīng)及其在血管性認(rèn)知障礙少突膠質(zhì)細(xì)胞損傷及修復(fù)中的作用進(jìn)行了綜述，在缺血性炎性損傷方面為未來有關(guān)血管性認(rèn)知障礙的基礎(chǔ)和臨床研究提供了參考。缺血缺氧對(duì)小膠質(zhì)細(xì)胞激活的調(diào)節(jié)機(jī)制、小膠質(zhì)細(xì)胞不同活化狀態(tài)相互轉(zhuǎn)化的機(jī)制以及OPCs分化成熟障礙的機(jī)制等值得更深入的研究。此外，小膠質(zhì)細(xì)胞激活介導(dǎo)的氧化應(yīng)激反應(yīng)等非炎性因素在血管性認(rèn)知障礙中的作用也值得進(jìn)一步研究。

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【點(diǎn)睛】

小膠質(zhì)細(xì)胞在腦缺血損傷后的極化（M1型與M2型）對(duì)腦白質(zhì)髓鞘損傷及修復(fù)具有不同作用和機(jī)制。本文對(duì)小膠質(zhì)細(xì)胞與血管性認(rèn)知障礙白質(zhì)損傷的關(guān)系進(jìn)行了綜述，為進(jìn)一步尋找血管性認(rèn)知障礙的治療靶點(diǎn)提供參考。