汪琦,朱舟,王偉

華中科技大學(xué)同濟(jì)醫(yī)學(xué)院附屬同濟(jì)醫(yī)院神經(jīng)科,武漢430030

1 CXCL12/CXCR4的生物學(xué)特性

趨化因子(chemotactic factor,CF)是一類小分子量(8～14 kDa)的分泌蛋白,最初研究發(fā)現(xiàn)其主要作用是調(diào)節(jié)白細(xì)胞的遷移,故命名為CF。根據(jù)N末端2個半胱氨酸殘基的空間位置不同可將CF分為CXC、CC、C和CX3C等4個亞族。CF受體為具有7個跨膜結(jié)構(gòu)的G蛋白偶聯(lián)受體,也可分為CXCR、CCR、XCR和CX3CR4類。

CXCL12又稱基質(zhì)細(xì)胞衍生因子-1(stromal cell derived factor-1,SDF-1),也稱為前B細(xì)胞刺激因子(pre-B cell stimulatory factor,PBSF),該細(xì)胞因子首先被發(fā)現(xiàn)是由骨髓基質(zhì)細(xì)胞所分泌,故命名。以前認(rèn)為CXCR4是CXCL12的唯一受體,但最近研究發(fā)現(xiàn)CXCL12可能存在另一受體CXCR7。生理狀況下CXCL12在外周如肺、肝、淋巴結(jié)、骨髓、腎上腺等多組織器官的基質(zhì)細(xì)胞持續(xù)表達(dá),而在中樞神經(jīng)系統(tǒng)(central nervous system,CNS)中主要由間質(zhì)細(xì)胞分泌;在病理情況下,如感染、腫瘤、卒中、炎癥時,則由星形膠質(zhì)細(xì)胞和血管內(nèi)皮細(xì)胞分泌。CXCR4在CNS的神經(jīng)元、星形膠質(zhì)細(xì)胞、小膠質(zhì)細(xì)胞、少突膠質(zhì)細(xì)胞和內(nèi)皮細(xì)胞上廣泛表達(dá)。在胚胎發(fā)育時期,骨髓基質(zhì)細(xì)胞分泌的CXCL12趨化造血干細(xì)胞由胚肝向骨髓遷移和定植[1]。在成熟個體,CXCL12在造血干細(xì)胞的向骨髓的歸巢過程中也發(fā)揮重要調(diào)節(jié)作用[2]。CXCL12在外周免疫系統(tǒng)中對淋巴細(xì)胞和單核細(xì)胞發(fā)揮濃度依賴的高效趨化作用參與炎癥免疫反應(yīng)。同時CXCL12也是調(diào)節(jié)B細(xì)胞前體細(xì)胞增殖的重要因子。其受體CXCR4是嗜T型HIV病毒感染T細(xì)胞的共受體。

CXCL12/CXCR4在CNS廣泛表達(dá),提示其可能存在著重要作用。CXCL12或CXCR4基因敲除的小鼠存在中樞和周圍神經(jīng)系統(tǒng)神經(jīng)元遷移障礙和軸索的投射異常,從而導(dǎo)致神經(jīng)系統(tǒng)發(fā)育障礙[3]。成熟腦組織不同區(qū)域的神經(jīng)干細(xì)胞上也廣泛表達(dá)CXCR4,病理情況下通過CXCL12濃度梯度趨化神經(jīng)干細(xì)胞向病灶遷移[4],以利于機(jī)體的修復(fù)。此外,CXCL12/CXCR4可能還通過間接(影響膠質(zhì)細(xì)胞谷氨酸釋放[5])和直接的(活化K+通道[6])方式參與調(diào)節(jié)神經(jīng)信號傳遞。

2 CXCL12/CXCR4與神經(jīng)系統(tǒng)疾病

2.1 HIV相關(guān)腦病 HIV感染后腦病是HIV患者死亡的最常見原因之一,其病理特點(diǎn)是神經(jīng)元的凋亡及神經(jīng)突觸和突觸小體結(jié)構(gòu)的消失。HIV主要通過感染小膠質(zhì)細(xì)胞和單核細(xì)胞進(jìn)入CNS。作為小膠質(zhì)細(xì)胞和星形膠質(zhì)細(xì)胞功能的延伸,CF及受體在神經(jīng)元的損傷和凋亡過程中起重要作用。CNS中與HIV神經(jīng)毒性相關(guān)的主要CF受體是CXCR4和CCR5。CXCR4通過G蛋白信號傳導(dǎo)系統(tǒng)Gi/Go的正負(fù)反饋調(diào)節(jié)機(jī)制完成信號轉(zhuǎn)導(dǎo),受體被激活后,細(xì)胞內(nèi)鈣離子濃度升高,誘發(fā)神經(jīng)細(xì)胞內(nèi)形成自由基(氧化亞氮和超氧陰離子)誘發(fā)凋亡[7]。CXCR4中和抗體可以抑制Caspase-3活化而降低神經(jīng)元凋亡[8]。研究發(fā)現(xiàn),艾滋病患者CNS內(nèi)巨噬細(xì)胞/小膠質(zhì)細(xì)胞和神經(jīng)元上CXCR4表達(dá)上調(diào)[9],而被感染的小膠質(zhì)細(xì)胞或巨噬細(xì)胞能促使星形膠質(zhì)細(xì)胞分泌CXCL12增加[10]。CXCL12和HIV病毒脫落蛋白gp120都是CXCR4受體激動劑。有研究認(rèn)為CXCL12可以促進(jìn)細(xì)胞存活,而gp120促進(jìn)細(xì)胞凋亡。gp120作用于CXCR4,引起細(xì)胞氧化損傷繼而激活 p53,提高神經(jīng)元內(nèi)凋亡蛋白活性因子-1(apoptosis protease activating factor 1,Apaf-1)的磷酸化水平;gp120還通過調(diào)節(jié)p53磷酸化水平來進(jìn)一步調(diào)節(jié)MDM-2和p21表達(dá),進(jìn)而誘導(dǎo)神經(jīng)細(xì)胞凋亡[11]。而CXCL12卻可以增強(qiáng)p53乙?；?促進(jìn)p21轉(zhuǎn)錄表達(dá)從而促進(jìn)細(xì)胞修復(fù)。但也有研究認(rèn)為gp120和CXCL12都能夠通過與神經(jīng)元上CXCR4結(jié)合直接導(dǎo)致神經(jīng)元的變性與凋亡[12],CXCL12非但不能阻止gp120的神經(jīng)毒性作用,還可通過刺激膠質(zhì)細(xì)胞活化間接引起神經(jīng)元凋亡[8]。還有研究發(fā)現(xiàn),gp120能夠通過CXCR4-NADPH氧化酶-過氧化物-中性鞘磷脂酶-神經(jīng)酰胺途徑導(dǎo)致神經(jīng)元凋亡。對于CXCR4信號途徑對神經(jīng)元的間接作用也有深入研究,gp120或CXCL12可通過活化星形膠質(zhì)細(xì)胞產(chǎn)生TNF-α,谷氨酸釋放,從而導(dǎo)致神經(jīng)元興奮性毒性損傷[13]。此外,HIV感染后的巨噬細(xì)胞能夠分泌前基質(zhì)金屬蛋白酶-2(pro-matrix metal proteinase-2,pro-MMP-2),該酶能被神經(jīng)元胞膜的1型基質(zhì)金屬蛋白酶(membrane-type 1 matrix metalloproteinase,MT1-MMP)活化,活化的MMP-2能夠分解CXCL12,分解產(chǎn)物CXCL12(5-67)通過結(jié)合CXCR3導(dǎo)致神經(jīng)元變性[14]?？傊?HIV感染可活化CXCR4,且能夠通過多種直接或間接的途徑引起神經(jīng)元損傷。目前對于CXCL12/CXCR4在HIV相關(guān)腦病中的作用仍然有待進(jìn)一步闡明,尤其是CXCL12在HIV相關(guān)腦病中的作用具有爭議。

2.2 腦部腫瘤 在腦部原發(fā)腫瘤如膠質(zhì)母細(xì)胞瘤、星形膠質(zhì)細(xì)胞瘤、成神經(jīng)管細(xì)胞瘤中均可見CXCL12和CXCR4表達(dá)上調(diào)。CXCR4主要表達(dá)于腫瘤細(xì)胞和部分內(nèi)皮細(xì)胞,并發(fā)生磷酸化活化。CXCL12則主要由內(nèi)皮細(xì)胞和侵入的小膠質(zhì)細(xì)胞分泌。在所有級別的星形膠質(zhì)細(xì)胞瘤的腫瘤細(xì)胞和血管內(nèi)皮細(xì)胞中均可見CXCR4的磷酸化活化[15],且CXCL12和CXCR4呈共定位表達(dá),表達(dá)的水平和腫瘤的惡性程度成正比,均表達(dá)于血管發(fā)生和退變、壞死及微囊改變的區(qū)域[16]。對來源于小腦外粒層的腫瘤研究發(fā)現(xiàn),由于CXCR4 mRNA的水平和神經(jīng)營養(yǎng)因子受體p75NTR、ATOH1及GLI1的表達(dá)顯著相關(guān),因此CXCR4也許可以作為一個有效的腫瘤標(biāo)志物[17]。CXCL12的表達(dá)還和腫瘤的病程密切相關(guān)。對裸鼠的研究顯示,CXCR4表達(dá)水平越高,膠質(zhì)瘤的生長速度和致死速度越快。在低級別膠質(zhì)瘤中,CXCL12可作為評價血管發(fā)生和腫瘤生長程度的非常有價值的指標(biāo),CXCL12和CXCR 4的表達(dá)導(dǎo)致腫瘤進(jìn)展時間縮短[18]。臨床分析也顯示,CXCR4陽性的膠質(zhì)瘤患者術(shù)后預(yù)后較差。在膠質(zhì)母細(xì)胞瘤細(xì)胞系培養(yǎng)時發(fā)現(xiàn),CXCL12能夠促進(jìn)腫瘤細(xì)胞DNA合成增加,誘導(dǎo)腫瘤細(xì)胞遷移[19]。小動物模型實(shí)驗(yàn)發(fā)現(xiàn)系統(tǒng)性給予CXCR4的拮抗劑AMD3100能夠通過增加腫瘤細(xì)胞凋亡和減少腫瘤細(xì)胞增殖抑制腫瘤生長。CXCL12和CXCR4還參與多種腫瘤的轉(zhuǎn)移過程,包括原位腫瘤細(xì)胞侵入血管、微環(huán)境下存活、運(yùn)動至靶器官、黏附及增殖等。有研究發(fā)現(xiàn)乳腺癌細(xì)胞利用CXCL12/CXCR4的細(xì)胞趨化功能實(shí)現(xiàn)腫瘤細(xì)胞的腦轉(zhuǎn)移[20]。因此,根據(jù)CXCL12和CXCR4的表達(dá)與腦部腫瘤惡性程度、進(jìn)展、轉(zhuǎn)移和預(yù)后的關(guān)系,提示它們也許能夠用于指導(dǎo)臨床對腦部腫瘤的監(jiān)測和治療。

2.3 卒中 卒中是神經(jīng)系統(tǒng)急性損傷,主要包括血栓形成、栓塞、系統(tǒng)低灌注、腦出血或蛛網(wǎng)膜下腔出血。在卒中的動物模型中,CXCL12在星形膠質(zhì)細(xì)胞和內(nèi)皮細(xì)胞中表達(dá)上調(diào)[21],而且CXCL12的上調(diào)和缺血損傷區(qū)域單核細(xì)胞的浸潤有關(guān),提示CXCL12可能參與炎癥病理過程[22]。在新生小鼠腦組織缺血缺氧情況下,地塞米松能下調(diào)CXCR4的表達(dá),影響炎癥級聯(lián)反應(yīng),從而發(fā)揮神經(jīng)保護(hù)作用[23]。此外,由于CXCL12對造血干細(xì)胞有強(qiáng)大的趨化作用,CXCL12/CXCR4被認(rèn)為參與造血源性的神經(jīng)前體細(xì)胞(neural progenitor cells,NPCs)由外周向中樞損傷部位的募集。Ceradini等[21]研究發(fā)現(xiàn),在腦組織局部缺血部位,CXCL12表達(dá)上調(diào),同時來自外周循環(huán)的CXCR4陽性的NPCs的粘附、遷移能力以及向病灶歸巢的能力均提高,而降低缺血局部CXCL12的水平,封閉NPCs上CXCR4受體,則可以阻止NPCs細(xì)胞向受損部位募集,不利于神經(jīng)功能修復(fù)。Robin等[4]的研究也證實(shí)缺血情況下CXCL12/CXCR4能夠特異性的介導(dǎo)NPCs進(jìn)入梗死灶。骨髓來源的干細(xì)胞進(jìn)入CNS后可能分化為神經(jīng)元或星形膠質(zhì)細(xì)胞,敲除小鼠CXCR4受體基因,腦梗死病灶周圍骨髓來源干細(xì)胞減少,神經(jīng)功能恢復(fù)受限[24]。此外,還有研究發(fā)現(xiàn)局部予以CXCL12能促進(jìn)內(nèi)皮前體細(xì)胞(endothelial progenitor cell,EPC)向缺血組織募集,有利于血管再生[25]。利用CXCL12調(diào)節(jié)造血來源的NPCs向卒中病灶處募集可能有助于神經(jīng)功能的恢復(fù)與重建。

2.4 多發(fā)性硬化(multiple sclerosis,MS)MS是CNS炎性脫髓鞘疾病,其特點(diǎn)是CNS多灶的髓鞘脫失,伴少突膠質(zhì)細(xì)胞的缺失和星形膠質(zhì)瘢痕形成。實(shí)驗(yàn)性自身免疫性腦脊髓炎(Experimental allergic encephalomyelitis,EAE)是MS的經(jīng)典小鼠動物模型。在MS和其他炎性神經(jīng)疾病患者的腦脊液中,可檢測到CXCL12[26]。在MS活動病灶處,星形膠質(zhì)細(xì)胞、血管腔及血管鞘的單核/巨噬細(xì)胞CXCL12表達(dá)水平增高,內(nèi)皮細(xì)胞的CXCL12相對較少。在靜止的MS病灶,內(nèi)皮細(xì)胞和星形膠質(zhì)細(xì)胞尤其是病灶邊緣增生的星形膠質(zhì)細(xì)胞可檢測到 CXCL12[26]。在EAE動物模型中,腦實(shí)質(zhì)細(xì)胞CXCR4水平上調(diào)[27]。McCandless等[28]研究發(fā)現(xiàn),正常情況下CXCL12表達(dá)于CNS內(nèi)皮細(xì)胞基底外側(cè)面,有助于限制CXCR4+單核細(xì)胞在血管內(nèi),抑制其向腦實(shí)質(zhì)內(nèi)擴(kuò)散,在 EAE模型中抑制CXCR4的活性,血管鞘明顯減少,而白質(zhì)內(nèi)單核細(xì)胞廣泛浸潤,炎癥反應(yīng)加重,促進(jìn)疾病進(jìn)展。對MS患者 CXCL12表達(dá)分布的進(jìn)一步研究發(fā)現(xiàn),活動性MS患者病灶處CXCL12表達(dá)分布發(fā)生變化,主要表達(dá)于小靜脈管腔內(nèi)側(cè),有助于白細(xì)胞的粘附和向腦實(shí)質(zhì)的遷移[29]。導(dǎo)致CXCL12表達(dá)分布發(fā)生變化的原因有待進(jìn)一步闡明。

2.5 阿爾茨海默病(Alzheimer's Disease,AD)

AD是老年人最常見的引起癡呆的原因,其病理特點(diǎn)為淀粉樣斑塊形成、神經(jīng)纖維纏結(jié)以及大量神經(jīng)元缺失,導(dǎo)致記憶及其他智力障礙。CXCL12是骨髓來源的CD34+干細(xì)胞最強(qiáng)的CF。這些干細(xì)胞不但具有很強(qiáng)的自我更新和造血分化潛能,而且在特定的外環(huán)境下可以橫向分化,如骨髓干細(xì)胞具有向血管內(nèi)皮細(xì)胞、神經(jīng)細(xì)胞等組織細(xì)胞轉(zhuǎn)化的能力。有研究對AD患者血清CXCL12水平進(jìn)行檢測,發(fā)現(xiàn)CXCL12明顯下降[30]。Parachikova等[30]進(jìn)一步研究發(fā)現(xiàn),予以小鼠 CXCR4的拮抗劑AMD3100,小鼠的學(xué)習(xí)和記憶功能下降。Ziabreva等[31]研究發(fā)現(xiàn),早期AD患者循環(huán)中CD34+干細(xì)胞減少,其室下區(qū)神經(jīng)干細(xì)胞數(shù)量亦明顯減少,而室下區(qū)是成熟腦組織中神經(jīng)元干細(xì)胞來源的主要場所。這些現(xiàn)象均提示AD患者可能缺乏造血干細(xì)胞支持。心肌梗死時,骨髓來源的內(nèi)皮前體細(xì)胞能夠被動員和募集到受損血管壁,修復(fù)血管或生成新的血管[32]。而AD患者同樣存在許多血管危險因素參與AD發(fā)病機(jī)制如腦血管淀粉樣變,加重癡呆癥狀。CXCL12能夠趨化骨髓來源的內(nèi)皮前體細(xì)胞結(jié)合到血管受損部位修復(fù)血管并促進(jìn)血管再生[33],外源性給予CXCL12能夠改善受損組織血液供應(yīng)[34]。此外,還有研究發(fā)現(xiàn)骨髓來源的前體細(xì)胞能夠進(jìn)入腦實(shí)質(zhì)并分化為小膠質(zhì)細(xì)胞,與腦內(nèi)固有的小膠質(zhì)細(xì)胞比較,骨髓來源的小膠質(zhì)細(xì)胞對Aβ具有更有效的吞噬能力[35],促進(jìn)骨髓來源的小膠質(zhì)細(xì)胞在向腦實(shí)質(zhì)募集,可以改善轉(zhuǎn)基因小鼠的認(rèn)知能力[36]。CXCL12可能參與骨髓來源小膠質(zhì)細(xì)胞向中樞神經(jīng)系統(tǒng)的募集,參與AD的疾病過程。

3 結(jié)論

作為神經(jīng)系統(tǒng)和免疫系統(tǒng)的一個橋梁,CXCL12/CXCR4在神經(jīng)免疫性疾病中的作用復(fù)雜而廣泛,而其具體的作用機(jī)制目前還知之甚少。闡明CXCL12在這些疾病中的作用,對深入了解這些疾病的發(fā)病機(jī)制有一定幫助,也可能為疾病的治療提供新的靶點(diǎn)。

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