鄒麗婷，莫念春(綜述)，鐘　玲(審校)

(重慶醫(yī)科大學(xué)附屬第二醫(yī)院腎內(nèi)科，重慶 400010)

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Fractalkine與ANCA相關(guān)性血管炎

鄒麗婷△，莫念春(綜述)，鐘玲※(審校)

(重慶醫(yī)科大學(xué)附屬第二醫(yī)院腎內(nèi)科，重慶 400010)

摘要：抗中性粒細(xì)胞胞質(zhì)抗體(ANCA)相關(guān)性血管炎是一類(lèi)累及多個(gè)器官系統(tǒng)的全身性自身免疫性疾病，它包括肉芽腫性多血管炎、顯微鏡下多血管炎和嗜酸性肉芽腫性多血管炎。該病進(jìn)展迅猛，病死率高，嚴(yán)重威脅人類(lèi)健康。Fractalkine是趨化因子CX3C亞家族中唯一的成員，CX3CR1是Fractalkine的特異性受體，兩者特異性結(jié)合后通過(guò)激活細(xì)胞內(nèi)的信號(hào)轉(zhuǎn)導(dǎo)通路參與免疫性疾病的發(fā)生與發(fā)展。該文就Fractalkine與ANCA相關(guān)性血管炎的最新研究進(jìn)展予以綜述。

關(guān)鍵詞：抗中性粒細(xì)胞胞質(zhì)抗體相關(guān)性血管炎；趨化因子；Fracktalkine；CX3CR1

趨化因子是一類(lèi)相對(duì)分子質(zhì)量為7 000～15 000、結(jié)構(gòu)相似和功能相關(guān)的多肽超家族,根據(jù)其N(xiāo)端保守半胱氨酸殘基的數(shù)目和間隔的結(jié)構(gòu)特點(diǎn)，可分為4個(gè)亞族：C、CC、CXC和CX3C；趨化因子和受體結(jié)合后，激活和趨化白細(xì)胞，吸引白細(xì)胞到炎癥反應(yīng)的靶部位，參與炎性疾病的發(fā)生、發(fā)展[1]。Fractalkine是CX3C亞族的唯一成員,是具有黏蛋白樣結(jié)構(gòu)的跨膜糖蛋白，具有介導(dǎo)細(xì)胞活化、趨化、黏附和遷移的功能[1-2]。近年發(fā)現(xiàn),在抗中性粒細(xì)胞胞質(zhì)抗體(anti-neutrophil cytoplasmic antibody，ANCA)相關(guān)性血管炎的發(fā)生、發(fā)展過(guò)程中，F(xiàn)ractalkine與其受體 CX3CR1結(jié)合后，增強(qiáng)CX3CR1+自然殺傷細(xì)胞的殺傷力，損傷內(nèi)皮細(xì)胞，血管壁發(fā)生纖維樣壞死；另外，介導(dǎo)CX3CR1+白細(xì)胞的趨化、黏附和遷移，使腎臟、皮膚和肺臟等靶器官發(fā)生炎癥反應(yīng)[3-4]?，F(xiàn)就Fractalkine與ANCA 相關(guān)性血管炎之間的關(guān)系進(jìn)行綜述。

1Fractalkine與CX3CR1

1.1Fractalkine的結(jié)構(gòu)、分布Fractalkine由397個(gè)氨基酸分子組成，從N端到C端分為5個(gè)區(qū)域：第1區(qū)域是N端24個(gè)氨基酸組成的信號(hào)肽序列；第2區(qū)域是由76個(gè)氨基酸組成的趨化因子功能域；第3區(qū)域是由241個(gè)氨基酸組成的富含甘氨酸、脯氨酸、絲氨酸和蘇氨酸的桿樣區(qū)域，其中包括17個(gè)退化的黏蛋白樣重復(fù)片段；第4區(qū)域是由18個(gè)氨基酸組成的跨膜疏水區(qū)；第5區(qū)域是由37個(gè)氨基酸殘基組成的胞質(zhì)區(qū)[2]。Fractalkine有膜結(jié)合型和可溶型兩種存在形式，膜結(jié)合型Fractalkine既能增強(qiáng)細(xì)胞黏附分子與整合素介導(dǎo)的細(xì)胞間黏附，又能在不依賴(lài)選擇素和整合素等黏附分子情況下，促進(jìn)內(nèi)皮細(xì)胞與CX3CR1+細(xì)胞的黏附[2，5-6]。膜結(jié)合型Fractalkine的近細(xì)胞膜側(cè)有一雙堿基的水解位點(diǎn)Thr-Arg-Arg-Gln (即338～341位氨基酸殘基)，可被金屬蛋白酶10、腫瘤壞死因子(tumor necrosis factor，TNF)α轉(zhuǎn)化酶和溶酶體半胱氨酸蛋白酶組織蛋白酶S水解成可溶型Fractalkine，介導(dǎo)白細(xì)胞的趨化[7-9]。在健康人體內(nèi)，F(xiàn)ractalkine在非造血細(xì)胞不表達(dá)或有極少量表達(dá)。Fractalkine在血管內(nèi)皮細(xì)胞和角化細(xì)胞等非造血細(xì)胞的表達(dá)受TNF-α、干擾素(interferon，INF)γ、白細(xì)胞介素(interleukin，IL)1和CD40等輔助性T細(xì)胞(helper T lymphocyte，Th)1型促炎因子的刺激而上調(diào)；相反，Th2型細(xì)胞因子(如轉(zhuǎn)化生長(zhǎng)因子β和IL-13)可抑制TNF-α和INF-γ誘導(dǎo)的Fractalkine的上調(diào)[9-10]。Foussat等[11]證實(shí)，B細(xì)胞在B細(xì)胞抗體和CD40刺激下表達(dá)Fractalkine。Lucas等[12]證實(shí)，樹(shù)突狀細(xì)胞在CD40信號(hào)刺激下表達(dá)Fractalkine。Sukkar等[9]證實(shí)，TNF-α和INF-γ通過(guò)激活p38絲裂原活化蛋白激酶和c-Jun 氨基末端激酶信號(hào)轉(zhuǎn)導(dǎo)通路誘導(dǎo)Fractalkine的表達(dá)。Chandrasekar等[13]研究證實(shí)，F(xiàn)ractalkine可激活結(jié)核毒素敏感G蛋白、磷脂酰肌醇3-激酶和核因子κB等,通過(guò)自分泌方式促進(jìn)自身表達(dá)。

1.2CX3CR1的結(jié)構(gòu)、分布Fractalkine的特異性受體CX3CR1，是由355個(gè)氨基酸組成的含有7個(gè)疏水性跨膜區(qū)段的單鏈?zhǔn)荏w，屬于七次跨膜G蛋白偶聯(lián)受體，分為細(xì)胞外區(qū)(趨化因子結(jié)構(gòu)區(qū))、跨膜區(qū)(疏水性氨基酸富含區(qū))和細(xì)胞內(nèi)區(qū)(信號(hào)轉(zhuǎn)導(dǎo)區(qū))三個(gè)功能區(qū)；CX3CR1分布在白細(xì)胞、血管內(nèi)皮細(xì)胞和纖維母細(xì)胞等細(xì)胞的表面[6，14-15]。Fractalkine與CX3CR1結(jié)合后,可以激發(fā)多通道的信號(hào)轉(zhuǎn)導(dǎo)途徑,從而激發(fā)許多蛋白激酶(如酪氨酸激酶、蛋白激酶B和絲裂原活化蛋白激酶等)[16-17]。Fractalkine/CX3CR1可激活絲裂原活化蛋白激酶信號(hào)通路,調(diào)控基因轉(zhuǎn)錄及表達(dá)，刺激細(xì)胞生長(zhǎng)及分化[18]；而Fractalkine與單核細(xì)胞、巨噬細(xì)胞和血管內(nèi)皮細(xì)胞上的CX3CR1結(jié)合后，可激活絲裂原活化蛋白激酶信號(hào)通路，促進(jìn)細(xì)胞遷移、黏附或增生[16，19]。文獻(xiàn)報(bào)道,Fractalkine/CX3CR1參與了許多臨床疾病的病理機(jī)制(如小血管炎、骨關(guān)節(jié)炎和腎小球腎炎等)[14-15，18]。

2Fractalkine與疾病

2.1Fractalkine與ANCA相關(guān)性血管炎ANCA相關(guān)性血管炎是一組以小血管壁的炎癥和纖維素樣壞死、血清中存在針對(duì)靶抗原蛋白酶3或髓過(guò)氧化物酶的ANCA陽(yáng)性為主要特征的系統(tǒng)性自身免疫性疾病，包括肉芽腫性多血管炎、顯微鏡下多血管炎和嗜酸性肉芽腫性多血管炎[20]。越來(lái)越多的研究證實(shí)，F(xiàn)ractalkine/CX3CR1參與ANCA相關(guān)性血管炎的發(fā)生、發(fā)展過(guò)程[3-4]。膜型Fractalkine主要分布在內(nèi)皮細(xì)胞表面,介導(dǎo)白細(xì)胞與內(nèi)皮細(xì)胞間的黏附,促進(jìn)白細(xì)胞在血管壁周?chē)木奂环置谛虵ractalkine由蛋白酶對(duì)膜型消化脫落形成,保留了趨化因子的功能,趨化白細(xì)胞向血管炎癥部位遷移[21]。Matsunawa等[4]發(fā)現(xiàn)，F(xiàn)ractalkine在大、中、小三類(lèi)血管炎患者的表達(dá)量較健康人都上調(diào)，在ANCA相關(guān)性血管炎患者的表達(dá)量高于其他類(lèi)型的血管炎患者，且以顯微鏡下多血管炎患者中表達(dá)最高；研究還發(fā)現(xiàn)，CX3CR1高表達(dá)于CD4+和CD8+T淋巴細(xì)胞。Morimura等[21]發(fā)現(xiàn)，顯微鏡下多血管炎患者的Fractalkine與CX3CR1的表達(dá)水平與伯明翰血管炎活動(dòng)性分?jǐn)?shù)、C反應(yīng)蛋白及紅細(xì)胞沉降率呈正相關(guān)，而且隨著藥物治療、臨床癥狀的緩解而逐漸降低。Bjerkeli等[3]發(fā)現(xiàn)，肉芽腫性多血管炎患者的Fractalkine與外周血單核細(xì)胞的CX3CR1表達(dá)水平同步上調(diào)，CX3CR1+CD3+CD4+T淋巴細(xì)胞和CX3CR1+單核細(xì)胞在全血中占的比例同時(shí)增加，從而保證了外周血單核細(xì)胞和淋巴細(xì)胞向血管病變部位的遷移及與內(nèi)皮細(xì)胞間的黏附；研究中還發(fā)現(xiàn)，F(xiàn)ractalkine和CX3CR1的表達(dá)水平既與顯微鏡下多血管炎和肉芽腫性多血管炎的嚴(yán)重程度呈正相關(guān)，又與抗凝血酶Ⅲ、纖維二聚體、血管性血友病因子及血漿血栓調(diào)節(jié)蛋白等內(nèi)皮細(xì)胞損傷標(biāo)志物的血清水平呈正相關(guān)。因此，F(xiàn)ractalkine可作為ANCA相關(guān)性血管炎，尤其是顯微鏡下多血管炎與肉芽腫性多血管炎的內(nèi)皮損傷標(biāo)志物及疾病活動(dòng)性和藥物治療效果的檢測(cè)指標(biāo)。CX3CR1高表達(dá)的淋巴細(xì)胞是ANCA相關(guān)性血管炎疾病不可或缺的效應(yīng)細(xì)胞，F(xiàn)ractalkine在肉芽腫性多血管炎的Th1細(xì)胞和內(nèi)皮細(xì)胞的相互作用中占主導(dǎo)地位。Lamprecht等[22]發(fā)現(xiàn)，肉芽腫性多血管炎的肉芽腫來(lái)源的T淋巴細(xì)胞及CD4+或CD8+T淋巴細(xì)胞在INF-γ刺激后分泌Th1型細(xì)胞因子，在肉芽腫性多血管炎患者的支氣管肺泡灌洗液中檢測(cè)到高表達(dá)的Th1型炎性因子IL-12。Csernok等[23]發(fā)現(xiàn)，肉芽腫性多血管炎患者的肉芽腫內(nèi)的炎性因子主要是Th1型細(xì)胞因子。Goda等[24]發(fā)現(xiàn)，細(xì)胞因子受體的表達(dá)決定著Th1和Th2細(xì)胞的細(xì)胞因子的作用范圍，CX3CR1主要表達(dá)于Th1細(xì)胞，與此同時(shí)，F(xiàn)ractalkine的主要效應(yīng)細(xì)胞是Th1細(xì)胞。Fractalkine和其特異性受體CX3CR1在類(lèi)風(fēng)濕關(guān)節(jié)炎的疾病活動(dòng)過(guò)程中也起著作用。Matsunawa等[14]在研究中將類(lèi)風(fēng)濕關(guān)節(jié)炎患者分為三組：①僅有關(guān)節(jié)病變的類(lèi)風(fēng)濕關(guān)節(jié)炎組；②有關(guān)節(jié)外表現(xiàn)：6個(gè)月內(nèi)有壞死性腎小球腎炎、周?chē)窠?jīng)病變、缺血性結(jié)腸炎及心包炎等，但無(wú)ANCA相關(guān)性血管炎相關(guān)的組織學(xué)改變的類(lèi)風(fēng)濕關(guān)節(jié)炎組；③既有關(guān)節(jié)外癥狀又有ANCA相關(guān)性血管炎的組織學(xué)改變的類(lèi)風(fēng)濕關(guān)節(jié)炎組；研究結(jié)果顯示，第3組患者的Fractalkine血清水平與伯明翰血管炎活動(dòng)性分?jǐn)?shù)及血清免疫復(fù)合物呈正相關(guān)，而與補(bǔ)體復(fù)合物呈負(fù)相關(guān)；研究中還發(fā)現(xiàn)，類(lèi)風(fēng)濕關(guān)節(jié)炎患者血清中的Fractalkine高表達(dá)，當(dāng)出現(xiàn)血管病變時(shí)Fractalkine的表達(dá)水平升高更明顯。有學(xué)者對(duì)類(lèi)風(fēng)濕關(guān)節(jié)炎外周血單核細(xì)胞的RNA研究發(fā)現(xiàn)，活動(dòng)期的類(lèi)風(fēng)濕關(guān)節(jié)炎患者的Fractalkine信使RNA水平上調(diào)，有血管損傷的患者其上調(diào)更顯著，隨著藥物治療，臨床癥狀的緩解，信使RNA及其蛋白表達(dá)水平逐漸降低；進(jìn)一步免疫組織化學(xué)結(jié)果提示，F(xiàn)ractalkine主要分布于動(dòng)脈血管內(nèi)皮細(xì)胞表面[22，24]。Fractalkine 引起單核細(xì)胞和內(nèi)皮細(xì)胞間的緊密黏附,既能通過(guò)Fractalkine本身的黏附功能實(shí)現(xiàn),也可通過(guò)激活整合素以提高整合素與其配體的親和力來(lái)實(shí)現(xiàn)。Goda等[24]研究也證實(shí)，F(xiàn)ractalkine通過(guò)內(nèi)皮細(xì)胞和CX3CR1+單核細(xì)胞間的黏附,參與血管損傷。這種黏附通過(guò)兩種途徑實(shí)現(xiàn)：①Fractalkine 自身具有的黏附功能；②Fractalkine增強(qiáng)新分離的單核細(xì)胞的纖維連接蛋白和細(xì)胞間黏附分子1的黏附[25]。Boehme等[26]研究證實(shí)，類(lèi)風(fēng)濕關(guān)節(jié)炎合并ANCA相關(guān)性血管炎患者血清中的Fractalkine上調(diào)趨勢(shì)與內(nèi)皮細(xì)胞損傷和血管炎癥的標(biāo)志物細(xì)胞間黏附分子1的上調(diào)趨勢(shì)一致。越來(lái)越多的研究證實(shí),炎性介質(zhì)IL-1β、TNF-α和脂多糖,通過(guò)核因子κB依賴(lài)機(jī)制顯著上調(diào)Fractalkine在內(nèi)皮細(xì)胞的表達(dá)；Fractalkine 與CX3CR1+自然殺傷細(xì)胞結(jié)合,以劑量依賴(lài)的方式增強(qiáng)自然殺傷細(xì)胞的殺傷力,導(dǎo)致內(nèi)皮細(xì)胞損傷，激發(fā)和促進(jìn)系統(tǒng)性小血管炎的病理生理過(guò)程[3，27]。

2.2Fractalkine與非血管炎疾病Fractalkine在腫瘤的發(fā)生、發(fā)展過(guò)程中，通過(guò)趨化自然殺傷細(xì)胞、樹(shù)突狀細(xì)胞和淋巴細(xì)胞等免疫細(xì)胞至腫瘤部位，減少浸潤(rùn)和轉(zhuǎn)移的發(fā)生。Xin等[28]證實(shí)，表達(dá)有Fractalkine的小鼠肺癌模型中，癌灶中有大量的自然殺傷細(xì)胞浸潤(rùn)，而浸潤(rùn)的自然殺傷細(xì)胞表現(xiàn)出了較強(qiáng)的殺傷活性。Nukiwa等[29]證實(shí)，把轉(zhuǎn)染Fractalkine基因的間充質(zhì)干細(xì)胞或樹(shù)突狀細(xì)胞接種到結(jié)腸癌和黑色素瘤小鼠體內(nèi)后發(fā)現(xiàn)，接種了經(jīng)Fractalkine修飾的腫瘤細(xì)胞，其癌巢中CD4+和CD8+T細(xì)胞大量聚集，抑制腫瘤的生長(zhǎng)，小鼠的生存時(shí)間延長(zhǎng)，而在CD4+T淋巴細(xì)胞缺陷或者CD8+T淋巴細(xì)胞缺陷的小鼠體內(nèi)卻沒(méi)有發(fā)現(xiàn)Fractalkine的這種抗腫瘤效應(yīng)。然而，有研究報(bào)道顯示，高表達(dá)的Fractalkine通過(guò)促進(jìn)瘤細(xì)胞和血管內(nèi)皮細(xì)胞間的黏附、誘導(dǎo)腫瘤新生血管的形成和介導(dǎo)瘤細(xì)胞的遷移，促進(jìn)浸潤(rùn)和轉(zhuǎn)移的發(fā)生[30-31]。Gao等[32]把表達(dá)Fractalkine分子的卵巢癌細(xì)胞株OV-HM接種到具有免疫力的小鼠體內(nèi)后發(fā)現(xiàn)，表達(dá)Fractalkine的腫瘤細(xì)胞聚集在血管周?chē)?，并且在腫瘤組織中還發(fā)現(xiàn)有大量的新生血管。在體外實(shí)驗(yàn)中，表達(dá)CX3CR1的前列腺癌細(xì)胞株P(guān)C3-ML細(xì)胞在流動(dòng)狀態(tài)能夠有效地黏附到骨髓內(nèi)皮細(xì)胞上，并且這種黏附作用可以被Fractalkine的中和抗體所阻斷；研究中還發(fā)現(xiàn)，PC3-ML 細(xì)胞還能沿著可溶性的Fractalkine的濃度梯度或者釋放Fractalkine的人類(lèi)成骨細(xì)胞的細(xì)胞培養(yǎng)液濃度梯度遷移[33]。Fractalkine兼有黏附和趨化的特性使其在腎小球這種高血流量組織中募集白細(xì)胞，趨化白細(xì)胞跨內(nèi)皮細(xì)胞轉(zhuǎn)運(yùn)，參與原發(fā)性腎病與繼發(fā)性腎臟疾病的病理過(guò)程。Segerer等[34]通過(guò)對(duì)多種腎病(包括胎兒腎、腎移植、腎腫瘤和各種腎小球腎疾病)的研究發(fā)現(xiàn)，大多數(shù)浸潤(rùn)腎小球和腎間質(zhì)的白細(xì)胞表達(dá)CX3CR1，而且CX3CR1+細(xì)胞與Fractalkine在腎臟內(nèi)炎癥中募集的細(xì)胞一致。各期系統(tǒng)性紅斑狼瘡腎病患者的腎穿刺結(jié)果顯示，系膜區(qū)和毛細(xì)血管壁上有大量的Fractalkine，F(xiàn)ractalkine的高表達(dá)與疾病的活動(dòng)程度呈正相關(guān)[35]。Furuichi等[36]研究證實(shí)，通過(guò)基因失活或通過(guò)目標(biāo)蛋白阻斷CX3CR1，既可以減少巨噬細(xì)胞的聚集，又能減少血小板源性生長(zhǎng)因子B和轉(zhuǎn)化生長(zhǎng)因子β的分泌與表達(dá)，從而減輕腎缺血/再灌注損傷后腎臟的炎癥和纖維化，恢復(fù)部分腎功能。

3小結(jié)

Fractalkine在ANCA相關(guān)性血管炎中的研究相對(duì)較少，目前它在ANCA相關(guān)性血管炎中的具體機(jī)制尚不清楚。研究表明，F(xiàn)ractalkine可能在ANCA相關(guān)性血管炎的發(fā)生、發(fā)展過(guò)程中介導(dǎo)白細(xì)胞與內(nèi)皮細(xì)胞間的黏附，趨化白細(xì)胞到血管病灶部位，促進(jìn)血管壁周?chē)仔约?xì)胞浸潤(rùn)，加速血管壁的纖維素樣壞死。因此，努力探索Fractalkine在ANCA相關(guān)性血管炎的具體作用機(jī)制，有望尋求ANCA相關(guān)性血管炎新的治療靶點(diǎn)和策略，并為相關(guān)疾病的防治提供新的線索。

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Fractalkine in ANCA-Associated VasculitisZOULi-ting,MONian-chun，ZHONGLing.(DepartmentofNephrology，theSecondAffiliatedHospitalofChongqingMedicalUniversity，Chongqing400010，China)

Abstract：Anti-neutrophil cytoplasmic antibody(ANCA)-associated vasculitis is a group of systemic autoimmune diseases，including granulomatosis with polyangiitis,microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis.People′s health is threatened by this disease,which is characterized by violent progression and high mortality.Fractalkine(CX3CL1)is the sole member of the CX3C chemokine family.CX3CR1 is the unique receptor for Fractalkine.In the occurrence and development of immunological diseases,cell signal transductive pathways are activated by Fractalkine via specific binding to CX3CR1.Here is to make a review of the latest advances of Fractalkine in ANCA-associated vasculitis.

Key words：ANCA-associated vasculitis； Chemokines; Fractalkine; CX3CR1

收稿日期：2014-12-17修回日期：2015-04-19編輯：鄭雪

doi：10.3969/j.issn.1006-2084.2015.20.010

中圖分類(lèi)號(hào)：R59

文獻(xiàn)標(biāo)識(shí)碼：A

文章編號(hào)：1006-2084(2015)20-3672-04