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Toll樣受體4與腸缺血再灌注損傷關(guān)系研究進(jìn)展①

2016-01-31 03:28:08鄭英強(qiáng),何延政,周翔宇
中國免疫學(xué)雜志 2016年1期
關(guān)鍵詞:補(bǔ)體亞群配體

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Toll樣受體4與腸缺血再灌注損傷關(guān)系研究進(jìn)展①

鄭英強(qiáng)何延政周翔宇

(瀘州醫(yī)學(xué)院附屬醫(yī)院甲狀腺血管外科,瀘州646000)

①本文受四川省教育廳資助項目(10ZB120、14TD0018)資助。

腸缺血在臨床上多見,病情復(fù)雜,處理較為棘手,缺乏早期的臨床診斷,一旦確診,多數(shù)已錯過最佳治療時間,容易發(fā)生再灌注損傷,引起全身炎癥反應(yīng)綜合征(Systemic inflammatory response syndrome,SIRS),甚至多器官功能衰竭(Multiple organ failure,MOF)及死亡[1]。缺血再灌注損傷的具體機(jī)制未明,越來越多的證據(jù)表明,與固有免疫的重要組成部分TLRs(Toll like receptors,TLRs)相關(guān),其中TLR4的作用尤為重要。本文就TLR4與腸缺血再灌注(Ischemia/Reperfusion,I/R)的關(guān)系作一綜述。

1腸缺血再灌注損傷

缺血性損傷發(fā)生在組織被暫時剝奪血液時,而再灌注損傷發(fā)生在血液重新供應(yīng)但觸發(fā)了一個強(qiáng)烈的炎癥反應(yīng),并可能導(dǎo)致最初并未缺血的組織損傷[2]。腸道是典型的缺血敏感性器官,造成腸道I/R損傷的原因大致可分為血管閉塞型和非閉塞型,閉塞型主要由某些栓子栓塞血管造成;最常見為非閉塞型,由于機(jī)體在遭受休克、敗血癥等刺激時,腸道的血液供應(yīng)會不成比例的嚴(yán)重下調(diào),以滿足心、腦的血液需求,導(dǎo)致腸缺血及后續(xù)的再灌注損傷的發(fā)生[3]。中性粒細(xì)胞的侵入被認(rèn)為是再灌注損傷的標(biāo)志之一,TLRs的下游通路控制著中性粒細(xì)胞化學(xué)趨化因子IL-8、G-CSF等的釋放,并直接引導(dǎo)中性粒細(xì)胞定位于缺血組織[4,5]。腸缺血再灌注損傷的機(jī)制未明,目前對其的研究大多是針對早期階段,其中TLRs的作用備受重視[6]。

2TLRs通路介紹

2.1TLRs通路總體介紹Toll樣受體(Toll like receptors,TLRs )是與果蠅Toll受體同源并表達(dá)于細(xì)胞膜上且與免疫系統(tǒng)識別病原微生物有關(guān)的一類受體家族,被認(rèn)為是目前哺乳動物中唯一可將細(xì)胞外抗原識別信息向胞內(nèi)傳遞,并引發(fā)針對該抗原特異性免疫反應(yīng)的關(guān)鍵跨膜蛋白。作為一種模式識別受體(Pattern recognition receptors,PRR),TLRs能夠識別病原體相關(guān)分子模式(Pathogen-associated molecular patterns,PAMPs),也被稱為TLRs的外源性配體,包括病毒、細(xì)菌、真菌等病原微生物的一些結(jié)構(gòu)組分和代謝產(chǎn)物[7]。不同的TLRs識別各自不同的PAMPs,其中TLR4可識別革蘭陰性菌胞壁的脂多糖(Lipopolysacchafide,LPS )、熱休克蛋白、呼吸道合胞病毒F蛋白等;近來研究發(fā)現(xiàn),TLRs也能識別機(jī)體在遭受無菌性刺激時主動分泌或被動釋放出來的內(nèi)源性分子,稱之為TLRs的內(nèi)源性配體,即損傷相關(guān)分子模式(Damage-associated molecular patterns,DAMPs),包括細(xì)胞外基質(zhì)分解產(chǎn)物、熱休克蛋白(Heat shock protein,HSP )、凋亡細(xì)胞某些胞膜成分及核酸等[8]。激活后的TLRs主要通過TIR區(qū)與胞漿內(nèi)的接頭蛋白MyD88(Myeloid differentiation protein 88 )C端上含有的TIR結(jié)構(gòu)域結(jié)合,再通過MyD88分子N端的死亡結(jié)構(gòu)域(Death domain,DD)募集下游含有DD的信號分子使信號下傳,轉(zhuǎn)錄因子p38/MAPK、NF-κB(Nuclear factor κB)和AP -1得以活化,誘導(dǎo)各種炎性因子的釋放,最終參與局部和全身炎癥反應(yīng)的發(fā)生[9]。MyD88的缺失將導(dǎo)致多種TLRs功能受損,如TLR2、TLR5、TLR7和TLR9,但并不是所有的TLRs通路都會被阻斷,如TLR4仍能識別LPS,激活下游炎癥通路。因此,TLRs信號通路的傳導(dǎo)包括MyD88依賴途徑和MyD88非依賴途徑,其中TLR4能分別利用這兩條途徑進(jìn)行信號的傳遞。TLR4下游NF-κB激活后可以導(dǎo)致炎癥因子及趨化因子的表達(dá)上調(diào),如TNF-α、IL-6、iNOS、ICAM等,且NF-κB還與細(xì)胞的凋亡、存活、生長、分裂相關(guān)。此外,TLR4還可以激活多個細(xì)胞內(nèi)信號系統(tǒng),包括ERK、JNK、MAPKs,這些信號涉及到細(xì)胞的炎癥、生存及死亡,且都參與了腸的I/R損傷[6]。TLRs介導(dǎo)固有免疫的作用發(fā)揮后,將進(jìn)一步誘導(dǎo)單核巨噬細(xì)胞系統(tǒng)及樹突狀細(xì)胞的活化成熟,促進(jìn)炎癥因子的釋放。

2.2TRLs 參與全身多處臟器的缺血再灌注損傷TLRs廣泛參與了全身多處臟器的缺血再灌注損傷,調(diào)控其的表達(dá)可顯著影響組織受損程度,如在肺中,短暫吸入NO可抑制TLR2/4信號,減少下游NF-κB介導(dǎo)的肺泡巨噬細(xì)胞促炎因子TNF-α的表達(dá),起到保護(hù)作用[10];在腦中,抑制TLR2/1與CD36的信號交聯(lián),或用低劑量的LPS刺激TLR4都可表現(xiàn)出神經(jīng)保護(hù)作用[11,12];在肝中,抑制TLR4/9可減少肝的損傷及細(xì)胞死亡、減少中性粒細(xì)胞的侵入、減少炎性因子的轉(zhuǎn)錄[13,14];在腎中,針對于TLR4的抑制治療可減少腎移植時缺血后的急性腎損傷,減少細(xì)胞凋亡數(shù)量[15,16];在心肌的缺血再灌注中,TLR2信號可導(dǎo)致左室功能失調(diào),抑制TLR2/4信號可減少NF-κB的核轉(zhuǎn)錄,減少炎癥介質(zhì)TNF-α、IL-1b、IL-6、MIP-1a、MIP-2、MCP-1等的釋放,減少心肌梗死面積[17-20]。

2.3TLRs在腸道中的表達(dá)及意義TLRs的表達(dá)分布廣泛,主要表達(dá)于單核細(xì)胞、巨噬細(xì)胞、T、B淋巴細(xì)胞及NK細(xì)胞等[21]。在腸道中,腸黏膜可表達(dá)TLR2與TLR4;腸上皮可表達(dá)TLR1、2、3、4、5、6、7、9;固有層單核細(xì)胞和平滑肌細(xì)胞可表達(dá)TLR4[6,22]??梢姡琓LR4相較于其他TLRs在腸道中具有最廣泛的表達(dá)。TLRs識別腸道中的病原相關(guān)分子,將信號轉(zhuǎn)化為抗菌肽的表達(dá)、黏膜屏障的建立和上皮細(xì)胞的增殖[23]。此外,腸上皮損傷過后的愈合及黏膜內(nèi)細(xì)菌的清除也都需要完整的TLRs信號。在正常情況下,由腸道上皮和巨噬細(xì)胞嚴(yán)密控制著TLR4的表達(dá)及活性,以此來維持腸道上皮對腸道菌群中的各類病原體的耐受,而不至于發(fā)生損傷性的炎癥反應(yīng)[24]。正常情況下,腸上皮細(xì)胞僅表達(dá)低水平的TLRs,當(dāng)受到損傷或炎癥刺激時,TLRs的表達(dá)會顯著增加[25,26]。

3TLR4參與腸缺血再灌注損傷

3.1腸缺血再灌注時TLR4的激活及信號傳導(dǎo)腸缺血再灌注時,TLR4可以通過外源性和內(nèi)源性配體被激活,首先,外源性配體(如細(xì)菌、病毒和真菌),包括跨過上皮屏障的共生菌及釋放的內(nèi)毒素可以激活TLR4,其中LPS(革蘭氏陰性菌細(xì)胞壁的主要成分)是TLR4的經(jīng)典配體[27]。其次,內(nèi)源性配體如高遷移率族蛋白1(High mobility group box-1 protein,HMGB1),以及由細(xì)胞死亡時的細(xì)胞碎片和細(xì)胞外基質(zhì)降解而來的產(chǎn)物如透明質(zhì)酸、纖連蛋白、硫酸肝素等,可以在無病原體存在的情況下激活TLR4誘導(dǎo)“無菌性損傷”[28,29]。在腸I/R時,MyD88途徑主要通過NF-κB介導(dǎo)大量的促炎因子如IL-1β、IL-6、TNF-α等的釋放、補(bǔ)體C3的沉積及前列腺素類物質(zhì)的產(chǎn)生,損傷作用明顯[30];在非MyD88通路中,主要是TRIF通路,可以介導(dǎo)干擾素調(diào)節(jié)因子3(Interferon regulatory factor 3,IRF3)的快速激活,導(dǎo)致干擾素β(Interferon-β)的釋放及延緩NF-κB的激活,保護(hù)作用明顯[31,32]。

3.2TLR4受缺血再灌注時腸道菌群環(huán)境變化的調(diào)控腸道是人體最大的儲菌庫,TLR2和TLR4選擇性識別穩(wěn)態(tài)環(huán)境下的共生菌,抵御外源性損傷,維持菌群環(huán)境的穩(wěn)定[33,34]。腸道遭受缺血再灌注損傷時,菌群環(huán)境會發(fā)生巨大改變,有研究表明,共生菌群引起TLR4的增加表達(dá),可減少Caspase-3的活性,使腸上皮細(xì)胞的凋亡減少,維持腸道GSH水平,抑制MDA和腸道通透性的增加,抑制NF-κB的活性[35]。針對腸I/R時抑菌治療的效果,目前存在分歧,有學(xué)者發(fā)現(xiàn)這會加重腸損傷[35],而其他學(xué)者卻發(fā)現(xiàn)這可減少TLR-2和TLR-4在腸道中的表達(dá),進(jìn)而減少TLR2和TLR4介導(dǎo)的炎癥介質(zhì)TNF-α、IL-6、COX-2的釋放,并可減少B細(xì)胞、抑制補(bǔ)體激活,而起到保護(hù)作用[36]。腸道屏障功能的破壞還可以讓腸道微生物直接易位于循環(huán)系統(tǒng),激活其他臟器的TLR4信號,誘導(dǎo)多臟器炎癥反應(yīng)[37-39]。

3.3TLR4調(diào)控腸缺血再灌注時炎癥反應(yīng)TLR4是啟動炎性反應(yīng)的跨膜蛋白之一,腸I/R時,TLR4的啟動可引起大量促炎因子如TNF-α、IL-1、IL-1β、IL-6、IL-8、iNOS等的級聯(lián)或放大,導(dǎo)致瀑布樣釋放,此外還可進(jìn)一步激活中性粒細(xì)胞等炎性細(xì)胞,釋放大量介質(zhì)如蛋白酶、氧自由基等,誘發(fā)細(xì)胞免疫,加重I/R損傷[40]。升高的TNF-α與IL-6是SIRS、MODS的一個標(biāo)志指標(biāo),預(yù)示著系統(tǒng)性炎性反應(yīng)及損傷的發(fā)生。作為腸缺血再灌注時TLR4的主要內(nèi)源性配體,HMGB1被證實(shí)是一種“晚期炎性反應(yīng)介質(zhì)”,可激活并放大炎性反應(yīng)。相反,TLR4的缺失會顯著抑制促炎通路NF-κB、P38 MAPK、AP-1的信號,減少炎性因子TNF-α、IL-6、MCP-1、MIP-2等的表達(dá),中性粒細(xì)胞的侵入也顯著減少。

3.4TLR4調(diào)控腸缺血再灌注時細(xì)胞凋亡腸I/R過程中會伴隨著大量的細(xì)胞死亡,研究顯示其中80%是以凋亡為主,且還會引起遠(yuǎn)隔器官出現(xiàn)凋亡改變[41-43],TLR4信號很可能在此過程中發(fā)揮著主導(dǎo)作用。適度凋亡對機(jī)體有益,一旦過量則會造成損傷。研究表明,TLR4參與了許多組織細(xì)胞的凋亡過程,如免疫細(xì)胞、肝細(xì)胞、氣道平滑肌細(xì)胞等。缺血再灌注時,TLR4可通過下游的MyD88依賴與非依賴途徑誘導(dǎo)細(xì)胞凋亡[44],產(chǎn)生的細(xì)胞因子TNF-α與IL-6也可促進(jìn)凋亡[45],同時HMGB1-TLR4信號軸可上調(diào)Caspase-8、CHOP和Bax,并進(jìn)一步影響線粒體功能,加劇凋亡,最終加劇細(xì)胞損傷。相反,TLR4的缺失可減少活化的Caspase-3表達(dá),增加Bcl-xl與Bax的結(jié)合率,緩解細(xì)胞凋亡[46]。此外,利用TLR4激動劑更可逆轉(zhuǎn)缺血后處理保護(hù)作用引起的Caspase-3下降趨勢,使凋亡再度增加。

3.5TLR4調(diào)控腸缺血再灌注時免疫應(yīng)答在先天免疫中,TLR4與補(bǔ)體信號之間存在交聯(lián)。補(bǔ)體是抗體發(fā)揮溶細(xì)胞作用的必要補(bǔ)充條件,可廣泛參與機(jī)體抗微生物防御反應(yīng)及免疫調(diào)節(jié),也可介導(dǎo)免疫病理的損傷反應(yīng)。正常情況下炎癥反應(yīng)僅發(fā)生在外來抗原侵入的局部,但在某些情況下補(bǔ)體介導(dǎo)的炎癥反應(yīng)也可對自身組織造成損傷。作為固有免疫的兩個主要成分,TLR4和補(bǔ)體都參與了腸道的I/R損傷,且很大程度上依賴于補(bǔ)體的激活,產(chǎn)生C3a與C5a化學(xué)趨化肽,增加LPS刺激時IL-6的產(chǎn)生,增強(qiáng)TLR4的功能發(fā)揮[47-49];TLR4的活化也可以上調(diào)補(bǔ)體蛋白的合成,補(bǔ)體與TLR4的相互促進(jìn)作用增強(qiáng)了局部的炎癥和損傷[47]。在野生型小鼠中證實(shí),用補(bǔ)體抑制劑可以顯著的減輕腸道缺血再灌注損傷。

在獲得性免疫中,TLR4可增強(qiáng)吞噬作用、抗原提呈作用及影響T細(xì)胞的表型分化[50,51]。Th表型是靜止T細(xì)胞被抗原刺激活化后的結(jié)果,目前研究證實(shí)Th1亞群可產(chǎn)生IFN-γ、IFN-β、IL-2,Th2亞群可產(chǎn)生IL-4、IL-5、IL-6和IL-13。IL-10在小鼠中被歸于Th2亞群因子,而在人類中,Th1和Th2亞群都能分泌IL-10。Th1和Th2亞群由于自身分泌的細(xì)胞因子的不同而表現(xiàn)出不同的免疫狀態(tài)。TLR4在腸I/R時T細(xì)胞活化后分化為不同Th亞群過程中,扮演著關(guān)鍵性導(dǎo)向作用,可使應(yīng)答向Th1亞群方向發(fā)展,而抑制Th2亞群作用,介導(dǎo)IFN-γ、IFN-β、IL-2的大量釋放,最終導(dǎo)致腸道的慢性炎癥狀態(tài)及損傷[52]。

3.6TLR4參與腸缺血再灌注時損傷的遠(yuǎn)隔播散腸在I/R時,充當(dāng)了MODS的始發(fā)器官,會通過血液循環(huán)及淋巴系統(tǒng),釋放大量的外源性配體(主要是LPS)及內(nèi)源性配體(主要是HMGB1),作為TLRs特別是TLR4的激動劑促進(jìn)局部及遠(yuǎn)隔臟器的炎癥損傷,表現(xiàn)為全身多器官功能障礙。這些因TLR4被激活而受到炎癥損傷的器官包括肝、肺、心、腦、腎等[53-55],諸多由TLR4誘導(dǎo)的炎性細(xì)胞和炎癥介質(zhì)通過不同的信號轉(zhuǎn)導(dǎo)途徑構(gòu)成炎癥反應(yīng)的“細(xì)胞網(wǎng)絡(luò)”和“生物介質(zhì)網(wǎng)絡(luò)”,直接參與多臟器損傷的發(fā)生發(fā)展。但目前還未有研究顯示肢體會受到此過程的影響。

3.7阻斷TLR4通路在腸缺血再灌注中的基礎(chǔ)研究通過各種途徑阻斷TLR4抑或是其下游信號,深入探討TLR4信號通路在腸I/R損傷中的作用機(jī)制,雖然尚處于基礎(chǔ)研究階段,但具有較為廣泛的應(yīng)用前景。研究發(fā)現(xiàn),抑制TLR4通路可以影響靜止T細(xì)胞的活化,使活化由Th1亞群向Th2亞群轉(zhuǎn)換,除了產(chǎn)生Th2亞群的因子,還會使保護(hù)因子HO-1、A20、BCL-1/BCL-XL等的表達(dá)上調(diào)而起到保護(hù)腸I/R損傷的作用[56]。TLR4的缺失可以改善有毒炎癥反應(yīng)[57],保護(hù)血源性休克導(dǎo)致的腸道損傷[58],包括降低TNF-α及IL-1β的水平,減少前列腺素的產(chǎn)生,降低微血管通透性。TLR4或下游的信號分子MyD88缺失后,腸道在遭受I/R時可以減少多形核白細(xì)胞的遷移、MPO水平及炎癥反應(yīng)的程度,減輕血管內(nèi)皮損傷,從而提高生存率[25,59]。在腸源性MODS中,抑制各臟器的TLR4信號,也都表現(xiàn)出類似的保護(hù)意義。但是,也有學(xué)者發(fā)現(xiàn)在TLR4缺陷的2周齡小鼠中,腸道遭受I/R時的損傷較野生組更重,其認(rèn)為這可能與缺乏TLR4后增加了腸道黏膜的壞死凋亡及炎癥因子的表達(dá)有關(guān),表現(xiàn)出TLR4本身的保護(hù)意義[60]。

4總結(jié)

毫無疑問,TLR4參與了腸缺血再灌注損傷,涉及到腸道局部及遠(yuǎn)隔臟器的損傷改變,調(diào)控TLR4信號可顯著影響腸缺血再灌注損傷的發(fā)生發(fā)展。

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[收稿2015-03-05]

(編輯張曉舟)

通訊作者及指導(dǎo)教師:周翔宇(1977年- ),男,博士,副教授,碩士生導(dǎo)師,主要從事缺血性疾病與先天免疫研究,E-mail: xiangyuzhou971@126.com。

作者簡介:鄭英強(qiáng)(1987年- ),男,碩士,主要從事腸缺血與先天免疫研究,E-mail: yingqiangzheng@126.com。

中圖分類號R656.7

文獻(xiàn)標(biāo)志碼A

文章編號1000-484X(2016)01-0131-05

doi:10.3969/j.issn.1000-484X.2016.01.031

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