自然殺傷細(xì)胞對(duì)肝星狀細(xì)胞的調(diào)控及其在肝纖維化中的作用

李天陽(yáng)， 涂正坤， 蘇立山

(吉林大學(xué)第一醫(yī)院轉(zhuǎn)化醫(yī)學(xué)研究院， 長(zhǎng)春 130021)

自然殺傷細(xì)胞對(duì)肝星狀細(xì)胞的調(diào)控及其在肝纖維化中的作用

李天陽(yáng)， 涂正坤， 蘇立山

(吉林大學(xué)第一醫(yī)院轉(zhuǎn)化醫(yī)學(xué)研究院， 長(zhǎng)春 130021)

肝星狀細(xì)胞(HSC)的激活與肝纖維化進(jìn)展有至關(guān)重要的聯(lián)系。作為固有免疫的重要組分， 自然殺傷細(xì)胞(NK細(xì)胞)在肝內(nèi)的富集程度更高，在機(jī)體防御病毒感染和腫瘤中發(fā)揮關(guān)鍵作用，而且其抗肝纖維化的功能也得到證實(shí)。NK細(xì)胞可以通過(guò)直接殺傷早期激活或衰老的HSC，或通過(guò)分泌IFNγ抑制肝纖維化。總結(jié)了最近幾年的相關(guān)研究進(jìn)展，以NK細(xì)胞和HSC的功能與表型為基礎(chǔ)，介紹了NK細(xì)胞調(diào)控HSC的分子免疫學(xué)機(jī)制及其潛在的抗肝纖維化作用。

肝硬化； 殺傷細(xì)胞, 天然； 肝星狀細(xì)胞； 綜述

至今為止肝纖維化是缺少有效治療手段的世界范圍健康難題[1]。多種原因會(huì)導(dǎo)致肝損傷，例如病毒感染(HBV、HCV)、藥物毒物(酒精為主)、代謝(非酒精性脂肪性肝病)以及自身免疫等。如果肝損傷持續(xù)存在，瘢痕組織會(huì)逐漸取代正常肝組織，這種慢性發(fā)展引起的病理性結(jié)果就是肝纖維化。肝纖維化最終發(fā)展為肝硬化，進(jìn)而引發(fā)肝衰竭，目前除肝移植外尚缺少有效的治療手段[2]。

肝纖維化過(guò)程伴隨著細(xì)胞外基質(zhì)(ECM)的堆積，而肝星狀細(xì)胞(HSC)是肝臟產(chǎn)生ECM的最主要細(xì)胞，其激活直接影響肝纖維化病理過(guò)程[3]。自然殺傷細(xì)胞(NK細(xì)胞)作為一種固有淋巴細(xì)胞，通過(guò)其自然殺傷功能和分泌功能，在機(jī)體對(duì)抗病毒感染和免疫監(jiān)視中發(fā)揮關(guān)鍵作用。本文總結(jié)了近幾年NK細(xì)胞與HSC關(guān)系的相關(guān)報(bào)道，詳細(xì)討論NK細(xì)胞對(duì)HSC的調(diào)控，及其在肝纖維化中扮演的角色。

1 肝星狀細(xì)胞(HSC)

在正常人肝臟中，HSC大約占肝內(nèi)細(xì)胞總量的5%～8%，通常分布于肝竇內(nèi)皮細(xì)胞與肝細(xì)胞之間。正常生理?xiàng)l件下，HSC參與肝臟的發(fā)育與重生、類維生素A代謝，以及肝臟的免疫調(diào)節(jié)。

激活后的HSC會(huì)分化為肌成纖維細(xì)胞，表達(dá)α-平滑肌動(dòng)蛋白。此外，激活的HSC合成I型膠原(包括α1和α2兩條鏈)，表達(dá)基質(zhì)金屬蛋白酶(MMP，特別是MMP-2)、TGFβ1、金屬蛋白酶組織抑制因子TIMP)1等[4]。激活后的HSC會(huì)在肝竇間隙中向周圍分泌ECM來(lái)逐漸填補(bǔ)肝細(xì)胞凋亡產(chǎn)生的空隙[5]。另一方面，激活后的HSC同時(shí)參與膠原的降解。MMP是一類鈣依賴性的特異性降解膠原及非膠原ECM成分的蛋白酶，在ECM的降解中發(fā)揮非常重要的作用。而HSC是MMP-2、MMP-9、MMP-13的重要來(lái)源[6]。但是，在表達(dá)MMP的同時(shí)，激活的HSC表達(dá)TIMP-1。TIMP-1通過(guò)抑制MMP的活性和HSC的凋亡發(fā)揮促纖維化作用[7]。

在病理情況下， HSC可以被多種炎性反應(yīng)的信號(hào)激活，例如：凋亡小體可以直接被HSC吞噬并激活HSC的促纖維發(fā)生基因的表達(dá)[8]；肝細(xì)胞和Kupffer細(xì)胞產(chǎn)生的活性氧可以通過(guò)還原型輔酶Ⅱ氧化酶激活HSC[9]；凋亡肝細(xì)胞的DNA也可以被HSC的Toll樣受體(TLR)9識(shí)別[10]等。一些細(xì)胞因子也參與HSC的激活(例如肝細(xì)胞和Kupffer細(xì)胞分泌的TGFβ)。此外，近期研究[11]發(fā)現(xiàn)HIV與HCV可以協(xié)同激活HSC的膠原與TIMP-1的表達(dá)。

2 NK細(xì)胞

NK細(xì)胞是固有免疫系統(tǒng)重要的組分，在對(duì)抗病毒感染和腫瘤中發(fā)揮重要作用，具有殺傷和分泌兩種主要功能。NK細(xì)胞具有特殊的識(shí)別感染細(xì)胞和腫瘤細(xì)胞的機(jī)制：基于其表面的抑制性受體(如殺傷細(xì)胞免疫球蛋白樣受體等)和激活性受體(NKG2D、NKp46等)，一系列信號(hào)決定了NK細(xì)胞對(duì)靶細(xì)胞的黏附、極化和脫顆粒效應(yīng)[12]。除了自然殺傷功能，NK細(xì)胞還可以通過(guò)其胞膜上表達(dá)的死亡受體配體(Fas ligand，F(xiàn)asL)和TNF相關(guān)凋亡誘導(dǎo)配體(TNF related apoptosis-inducing ligand，TRAIL)激活靶細(xì)胞上對(duì)應(yīng)受體直接發(fā)揮殺傷功能。

肝內(nèi)NK細(xì)胞是一類組織特異性的NK細(xì)胞。人肝臟內(nèi)NK細(xì)胞約占所有肝淋巴細(xì)胞的30%～50%，而外周血中NK細(xì)胞的比例只有10%。除了數(shù)量上的差別，肝內(nèi)NK細(xì)胞的表型也與外周血中不同：肝內(nèi)NK細(xì)胞大多數(shù)是CD56brightCD16-，相對(duì)而言成熟程度較低[13]；高表達(dá)CD11a，與其在肝內(nèi)和Kupffer細(xì)胞的黏附有關(guān)[14]；高表達(dá)TRAIL[15]。功能上，肝內(nèi)NK細(xì)胞具有更強(qiáng)的分泌功能，包括IFNγ、TNFα、粒細(xì)胞-巨噬細(xì)胞集落刺激因子等；但脫顆粒效應(yīng)弱于外周血NK細(xì)胞[16]。事實(shí)上，外周血NK細(xì)胞與肝內(nèi)NK細(xì)胞并不是相互孤立的，在生理狀態(tài)下，存在NK細(xì)胞在組織與外周血之間的再循環(huán)[17]；在肝臟發(fā)生炎癥反應(yīng)時(shí)，外周血NK細(xì)胞會(huì)在肝臟中累計(jì)[18]，而來(lái)自于外周血的NK細(xì)胞也會(huì)發(fā)揮抑制肝纖維化的作用[19]。

肝內(nèi)NK細(xì)胞在肝臟腫瘤和病毒感染中扮演著重要角色。肝內(nèi)NK細(xì)胞可以通過(guò)細(xì)胞毒性作用抑制肝腫瘤細(xì)胞的轉(zhuǎn)移[20]。而肝內(nèi)NK細(xì)胞的數(shù)量以及NK細(xì)胞功能相關(guān)基因也與原發(fā)性肝癌患者的生存期相關(guān)[21]。此外，肝內(nèi)NK細(xì)胞在對(duì)抗HBV/HCV感染中也通過(guò)細(xì)胞毒性和IFNγ發(fā)揮重要作用。NK細(xì)胞IFNγ分泌功能受損與HCV清除之間有直接關(guān)系[22]；HCV感染者體內(nèi)CD56neg NK細(xì)胞的比例升高，而這一亞群的NK細(xì)胞殺傷和分泌能力較弱[23]。阻斷抑制性受體NKG2A，可以激活NK細(xì)胞，促進(jìn)HBV的清除[24]。

3 NK細(xì)胞對(duì)HSC激活的調(diào)控在肝纖維化發(fā)病機(jī)制中的作用

早在2006年就有報(bào)道[25-26]小鼠 NK細(xì)胞可以通過(guò)殺傷HSC抑制肝纖維化。隨后幾年中，關(guān)于NK細(xì)胞殺傷HSC的報(bào)導(dǎo)逐漸增多，在肝纖維化患者中得到驗(yàn)證，其機(jī)制也逐漸清晰[27]。

3.1 NK細(xì)胞通過(guò)細(xì)胞毒性作用殺傷激活的HSC NK細(xì)胞對(duì)激活后HSC的殺傷功能最早報(bào)導(dǎo)于2006年[25-26]。隨后在各種動(dòng)物模型、人原代細(xì)胞或細(xì)胞系中均得到驗(yàn)證，NK細(xì)胞殺傷HSC的機(jī)制也慢慢清晰[28]。這些研究證明NK細(xì)胞選擇性殺傷早期激活或者晚期激活的HSC，而不會(huì)對(duì)未激活的HSC產(chǎn)生細(xì)胞毒性。

其中，小鼠和人原代細(xì)胞的研究都傾向于NKG2D在NK細(xì)胞識(shí)別殺傷HSC上發(fā)揮重要的作用[26,29-30]。NKG2D是NK細(xì)胞重要的激活性受體，參與自然殺傷功能。小鼠的HSC表達(dá)視黃酸早期轉(zhuǎn)錄因子1(NKG2D的配體)，并且在激活后表達(dá)升高[26]，同樣，人HSC表面高表達(dá)MHC Ⅰ類分子相關(guān)蛋白A/B和UL16結(jié)合蛋白2(均是NKG2D配體)[30]。無(wú)論是在小鼠還是人原代細(xì)胞的實(shí)驗(yàn)中，使用抗體阻斷NKG2D，均能抑制NK細(xì)胞誘導(dǎo)的HSC凋亡[26，29-30]。NKG2D識(shí)別激活之后，NK細(xì)胞通過(guò)脫顆粒效應(yīng)，包括顆粒酶B，直接殺傷激活的HSC[25，30]。此外，小鼠體內(nèi)實(shí)驗(yàn)[31]證實(shí)，抑制NK細(xì)胞的殺傷細(xì)胞免疫球蛋白樣受體(識(shí)別MHC-I，NK細(xì)胞的抑制性受體)，NK細(xì)胞殺傷HSC的能力增強(qiáng)。

另一方面，TRAIL和FasL也在NK細(xì)胞誘導(dǎo)HSC凋亡的過(guò)程中發(fā)揮重要作用[26，30]。激活的HSC高表達(dá)TRAIL的受體TRAIL-R2(即death receptor 5，DR5)[30，32-33]。TRAIL結(jié)合DR5后，通過(guò)募集Fas相關(guān)死亡結(jié)構(gòu)域蛋白和caspase-8來(lái)組成死亡誘導(dǎo)信號(hào)復(fù)合體，進(jìn)而激活下游的caspase-3/-6/-7，誘導(dǎo)細(xì)胞凋亡[34]。通過(guò)抗體阻斷TRAIL，同樣可以抑制NK細(xì)胞誘導(dǎo)的HSC凋亡[26，30，35]。另一方面，HSC表達(dá)死亡受體[32]，在人原代細(xì)胞的體外實(shí)驗(yàn)[30]中，抑制FasL能部分降低HSC的凋亡。

3.2 NK細(xì)胞通過(guò)分泌IFNγ抑制HSC的激活 IFNγ是一種抑制肝纖維化的細(xì)胞因子，可以通過(guò)其受體(IFNGR)下游的STAT1直接抑制HSC的激活和增殖，誘導(dǎo)HSC的凋亡[36]，并且能夠抑制TGFβ/Smad3對(duì)HSC的激活[37]。而NK細(xì)胞是主要的IFNγ分泌細(xì)胞之一[38]，肝內(nèi)NK細(xì)胞相較于外周血NK細(xì)胞，具有更強(qiáng)的IFNγ分泌功能[39]。甚至于，利用包含IFNγ的脂質(zhì)體，靶向HSC的體內(nèi)治療方案，在肝纖維化大鼠模型中取得很好的效果[40]。除了直接抑制HSC，IFNγ還可以增強(qiáng)NK細(xì)胞對(duì)HSC的殺傷功能[26，36]，這可能與IFNγ促進(jìn)NK細(xì)胞TRAIL表達(dá)有關(guān)[41]。

3.3 其他細(xì)胞參與的NK-HSC的調(diào)控 除了NK細(xì)胞，亦有多種免疫細(xì)胞可以通過(guò)分泌細(xì)胞因子或趨化因子的方式參與對(duì)HSC激活的調(diào)節(jié)。例如，Kupffer細(xì)胞和單核細(xì)胞可以通過(guò)多種方式調(diào)控HSC(如通過(guò)活性氧和TGFβ促進(jìn)HSC激活[42-43])；其分泌的血小板衍生因子也是一種主要的促分裂趨化因子[44]。Th1細(xì)胞通過(guò)分泌IFNγ抑制HSC的膠原合成[45]；Th2細(xì)胞通過(guò)IL-4和IL-13直接誘導(dǎo)HSC激活，并且可以通過(guò)誘導(dǎo)Kupffer細(xì)胞分泌血小板衍生因子和TGF-β促進(jìn)肝纖維化[46]。Treg細(xì)胞和Kupffer細(xì)胞分泌的IL-10能夠促進(jìn)激活的HSC衰老[47]。

除了直接的NK細(xì)胞和HSC之間作用的研究外，更復(fù)雜的三種細(xì)胞之間的作用也有報(bào)道。在小鼠的代謝性肝損傷模型[19]中，NKp46+NK細(xì)胞通過(guò)分泌IFNγ促進(jìn)M1型巨噬細(xì)胞極化，抑制纖維化。此外，HIV/HCV合并感染者的纖維化進(jìn)程加快，可能與CD4+T淋巴細(xì)胞缺失導(dǎo)致的IL-2水平下降，繼而影響NK細(xì)胞的殺傷功能有關(guān)[48]。Treg可以通過(guò)T淋巴細(xì)胞抗原4和TGF-ss1/IL-8，降低NK細(xì)胞對(duì)HSC的殺傷[49]。

3.4 NK細(xì)胞在肝纖維化中的作用 通過(guò)動(dòng)物肝纖維化造模，敲除/抑制/增強(qiáng)NK細(xì)胞的方式，觀察小鼠的纖維化進(jìn)展可以推斷NK細(xì)胞發(fā)揮的作用。相較于CD8+T淋巴細(xì)胞或NKT細(xì)胞，小鼠肝內(nèi)NK細(xì)胞比例的下降明顯會(huì)增加小鼠肝內(nèi)Ⅰ型膠原[50]。抑制小鼠NK細(xì)胞的殺傷細(xì)胞免疫球蛋白樣受體(抑制性受體)，可以明顯降低纖維化造模小鼠的肝組織α-平滑肌動(dòng)蛋白和mRNA水平[31]。清除小鼠體內(nèi)的NK細(xì)胞，會(huì)造成小鼠肝內(nèi)膠原的堆積[28]。

盡管在動(dòng)物模擬的體內(nèi)環(huán)境中已經(jīng)證實(shí)了NK細(xì)胞發(fā)揮的抗纖維化作用，但是由于患者的病因更復(fù)雜，NK細(xì)胞是否會(huì)在特定環(huán)境下促進(jìn)纖維化，仍值得討論[27，33]。近期有報(bào)導(dǎo)[51]指出Nkp44+TNFα+的NK細(xì)胞在肝內(nèi)的數(shù)量與HCV感染者的肝損傷和纖維化程度呈正相關(guān)。此外，在急性發(fā)作的乙型肝炎患者體內(nèi)發(fā)現(xiàn)NK細(xì)胞高表達(dá)TRAIL，并能直接殺傷肝細(xì)胞[52]。HBV感染者肝細(xì)胞高表達(dá)TRAIL受體也已經(jīng)證實(shí)[53]。與CCl4或膽管結(jié)扎引起的肝損傷不同，被病毒感染的肝細(xì)胞會(huì)被NK細(xì)胞識(shí)別殺傷[53]，可能通過(guò)NK細(xì)胞引起的肝細(xì)胞凋亡，誘導(dǎo)HSC的激活[8]進(jìn)而產(chǎn)生促進(jìn)纖維化的作用。

4 靶向NK-HSC治療纖維化及臨床應(yīng)用和前景

除了動(dòng)物模型和體外實(shí)驗(yàn)，臨床上也有不少NK細(xì)胞抑制肝纖維化的證據(jù)。HCV慢性感染者中，NK細(xì)胞的活力與肝纖維化的程度呈負(fù)相關(guān)[54]，纖維化程度更高的患者NK細(xì)胞體外誘導(dǎo)HSC凋亡的能力更弱[30]。使用IFNα治療肝纖維化，可以觀察到HSC的增殖與激活被抑制，這一過(guò)程中，NK細(xì)胞可能發(fā)揮重要作用，因?yàn)镮FNα可以提高NK細(xì)胞的TRAIL表達(dá)，從而增強(qiáng)NK細(xì)胞殺傷HSC的能力[55]。

目前為止，尚未有在患者中直接靶向NK細(xì)胞的纖維化治療報(bào)導(dǎo)。不過(guò)，NK細(xì)胞直接抑制纖維化的功能比較清楚，并非單核/巨噬細(xì)胞或Treg細(xì)胞的雙面作用。另外，NK細(xì)胞無(wú)論是體外擴(kuò)增回輸[56]，還是通過(guò)細(xì)胞因子的體內(nèi)激活[57]都已經(jīng)應(yīng)用于臨床治療或臨床試驗(yàn)。另一方面，相較于臨床常用的抑制TGFβ信號(hào)通路的策略，NK細(xì)胞作為靶點(diǎn)選擇性更高，不會(huì)殺傷靜息狀態(tài)的HSC以及其他肝內(nèi)正常細(xì)胞，還可以同時(shí)起到抗腫瘤和抗病毒的作用[35]。NK細(xì)胞仍有作為肝纖維化治療靶點(diǎn)的潛力。

由于IFNα、IFNγ、poly I∶C都可以激活NK細(xì)胞的TRAIL表達(dá)，增強(qiáng)NK細(xì)胞的細(xì)胞毒性，進(jìn)而通過(guò)NK細(xì)胞調(diào)控HSC激活[58-59]，并且它們抑制肝纖維化的作用比較清楚[26]，已經(jīng)用于抗病毒/抗腫瘤的臨床治療或臨床前研究[57,60]，所以IFNα、IFNγ、poly I∶C可能會(huì)是靶向NK-HSC的較好選擇。

5 小結(jié)

總的來(lái)說(shuō)，NK細(xì)胞直接抑制HSC主要通過(guò)兩方面：(1)通過(guò)NKG2D/TRAIL/FasL直接殺傷激活的HSC；(2)NK細(xì)胞分泌的IFNγ是一種抗纖維化因子。除了NK-HSC的直接作用，NK細(xì)胞與其他免疫系統(tǒng)組分之間的相互調(diào)節(jié)也會(huì)影響纖維化進(jìn)展，這也是最近的研究熱點(diǎn)。此外，盡管目前尚未有靶向NK細(xì)胞的纖維化臨床治療的報(bào)導(dǎo)，但大多數(shù)文獻(xiàn)都肯定了NK細(xì)胞的抗纖維化作用。

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引證本文：LI TY, TU ZK, SU LS. Regulatory effect of natural killer cells on hepatic stellate cells and their role in liver fibrosis[J]. J Clin Hepatol, 2017, 33(3): 558-562. (in Chinese)

李天陽(yáng)， 涂正坤， 蘇立山. 自然殺傷細(xì)胞對(duì)肝星狀細(xì)胞的調(diào)控及其在肝纖維化中的作用[J]. 臨床肝膽病雜志, 2017, 33(3): 558-562.

(本文編輯：王亞南)

Regulatory effect of natural killer cells on hepatic stellate cells and their role in liver fibrosis

LITianyang,TUZhengkun,SULishan.

(ResearchInstituteofTranslationalMedicine,TheFirstHospitalofJilinUniversity,Changchun130021,China)

Hepatic stellate cell (HSC) activation is closely associated with the progression of liver fibrosis. As an important component of the innate immune system, natural killer (NK) cells are enriched in the liver and play a key role in host defense against viral infection and tumor, and their anti-fibrotic effect has also been confirmed. NK cells can reduce liver fibrosis by killing early-activated or senescent HSCs or secreting interferon-γ. This article summarizes related research advances in recent years, and introduces the molecular immunological mechanism of NK cells in regulating HSCs and their potential anti-fibrotic effect based on the function and phenotype of NK cells and HSCs.

liver cirrhosis; killer cells, natural; hepatic stellate cells; review

10.3969/j.issn.1001-5256.2017.03.036

2016-12-15；

2017-01-18。

國(guó)家自然科學(xué)基金(81373143,81571535)

李天陽(yáng)(1992-)，男，主要從事自然殺傷細(xì)胞與肝星狀細(xì)胞的相關(guān)研究。

涂正坤，電子信箱: tuzhengkun@hotmail.com;蘇立山，電子信箱: 3158383517@qq.com。

R575.2

A

1001-5256(2017)03-0558-05