STING信號通路在肝臟疾病中的作用及研究進(jìn)展

0 引言

常見的肝臟疾病包括病毒性肝炎、酒精性肝病(alcoholic liver disease,ALD)、非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)以及相關(guān)的肝纖維化、肝硬化和肝細(xì)胞癌(hepatocellular carcinoma,HCC)等.由于肝臟疾病的病理機(jī)制復(fù)雜,其發(fā)生與發(fā)展是多因素、多步驟的復(fù)雜過程,藥物及手術(shù)治療存在一定的局限性,肝移植是終末期肝病唯一有效的治療方法,但肝源的缺乏和終身用藥的副作用限制了其應(yīng)用.因此,積極探索肝臟疾病的病理機(jī)制及藥物治療方法具有重要意義.已有證據(jù)表明cGAS-STING信號通路參與多種肝臟疾病的病理過程,它觸發(fā)了與自噬、免疫逃逸和有絲分裂相關(guān)的炎癥風(fēng)暴,同時(shí)在宿主抵抗病毒和細(xì)菌入侵過程也起到至關(guān)重要的作用,是目前肝臟疾病機(jī)制及治療研究的一個重要潛在方向.

1 cGAS-STING信號通路概述

STING(stimulator of interferon genes,STING),也稱干擾素激活基因,首次在2008年被揭示是先天性免疫信號的調(diào)節(jié)劑.cGAS-STING信號通路是天然免疫領(lǐng)域的重大發(fā)現(xiàn).當(dāng)存在病毒或其他致病因素所導(dǎo)致的細(xì)胞DNA損傷時(shí),損傷的DNA會誘導(dǎo)環(huán)狀GMP-AMP合成酶(cyclic GMP-AMP synthase,cGAS)構(gòu)象變化,并催化環(huán)鳥嘌呤腺嘌呤(cyclic GMP-AMP,cGAMP)的產(chǎn)生.cGAMP作為第二信使,招募位于內(nèi)質(zhì)網(wǎng)上的效應(yīng)器蛋白STING,促進(jìn)STING從內(nèi)質(zhì)網(wǎng)通過高爾基體到核周圍的運(yùn)輸,STING作為通路的關(guān)鍵效應(yīng)蛋白,會促使TANK結(jié)合激酶1(TANK-bingding kinase 1,TBK1)磷酸化激活,隨后一方面促進(jìn)干擾素調(diào)節(jié)因子3(interferon regulatory factor 3,IRF3)核轉(zhuǎn)位,產(chǎn)生Ⅰ型干擾素(interferons,IFNs);另一方面,STING會活化IκB激酶(inhibitor of nuclear factor kappa-B kinase,IKK),IKK將細(xì)胞內(nèi)NF-κB-IκB復(fù)合物的IκB亞基調(diào)節(jié)位點(diǎn)的絲氨酸磷酸化,進(jìn)而被蛋白酶降解,從而釋放NF-κB二聚體進(jìn)入細(xì)胞核,與有NF-κB結(jié)合位點(diǎn)的基因結(jié)合,啟動轉(zhuǎn)錄進(jìn)程,促進(jìn)炎性因子分泌,發(fā)揮促進(jìn)炎癥的作用

.由于STING在多種細(xì)胞類型中廣泛表達(dá),并能調(diào)控不同的程序性細(xì)胞死亡途徑,所以對cGASSTING信號通路的認(rèn)識在過去十年中迅速增長,許多研究表明cGAS-STING信號通路參與多種疾病,包括炎癥、感染、自身免疫性疾病、代謝紊亂和腫瘤等

.最近的研究表明

,cGAS-STING信號通路也參與了病毒性肝炎、ALD、NAFLD、肝損傷和HCC等多種疾病的病理過程,我們總結(jié)了cGAS-STING信號通路在多種肝臟疾病中的作用及其潛在治療意義,深入了解cGAS-STING信號通路可能為治療肝臟疾病提供新的思路.

2 cGAS-STING信號通路與肝臟疾病

2.1 cGAS-STING信號通路與慢性肝炎 病毒性肝炎是一個重大的公共衛(wèi)生問題,從流行趨勢來看,乙型肝炎病毒(hepatitis B virus,HBV)與丙型肝炎病毒(hepatitis C virus,HCV)仍是慢性肝炎、肝硬化和HCC最重要的致病因素

.因此,探討HBV感染的細(xì)胞內(nèi)分子機(jī)制至關(guān)重要.有研究報(bào)道顯示cGAS-STING信號通路有著優(yōu)越的抗病毒能力,可檢測細(xì)胞質(zhì)中的病毒DNA,如單純皰疹病毒-1、人類免疫缺陷病毒、腺病毒、人類巨細(xì)胞病毒等

.當(dāng)然,除了識別DNA病毒,它也可以識別并抵抗RNA病毒,特別是陽性的單鏈RNA(single stranded RNA,ssRNA)病毒

.在對HBV的研究過程中,有研究者發(fā)現(xiàn)cGAS-STING信號通路通過激活下游Toll樣受體3(toll-like receptor 3,TLR3)產(chǎn)生干擾素β(interferon β,IFN-β)抑制HBV的復(fù)制

.另一方面,HBV可逃避cGAS效應(yīng)通路及免疫系統(tǒng)的識別和攻擊,導(dǎo)致肝細(xì)胞慢性感染,例如HBV聚合酶可破壞STING的K63泛素化,并通過與STING相互作用最終抑制IFN-Ⅰ的產(chǎn)生

.Hu等

將HBV病毒質(zhì)粒(pHBv1.3)與表達(dá)cGAS和STING質(zhì)粒共轉(zhuǎn)染至HepG2細(xì)胞,發(fā)現(xiàn)當(dāng)HepG2細(xì)胞被共轉(zhuǎn)染后,乙肝病毒RNA水平顯著降低,而HBV DNA水平和e抗原分泌減少5倍,乙肝病毒RNA在細(xì)胞中比例明顯減少,并且在人肝細(xì)胞系L02和pHBV1.3轉(zhuǎn)染的小鼠模型中也獲得了類似的結(jié)果.相比于肝細(xì)胞,Kupffer細(xì)胞(kupffer cells,KCs),即肝巨噬細(xì)胞有更高的STING蛋白表達(dá)量,它可以吞噬病毒感染細(xì)胞,減輕機(jī)體病毒攜帶量,但同時(shí),HBV病毒核心也可以通過cGAS-STING信號通路激活Kupffer細(xì)胞上的Toll樣受體2(toll-like receptor 2,TLR2),并通過產(chǎn)生白介素10(interleukin 10,IL-10)抑制HBV特異性T細(xì)胞應(yīng)答

.肝細(xì)胞中cGAS-STING表達(dá)水平的降低以及針對cGAS-STING信號轉(zhuǎn)導(dǎo)的HBV逃逸機(jī)制在一定程度上促進(jìn)了肝細(xì)胞慢性HBV感染.在HCV與STING相關(guān)的研究中.有報(bào)道稱HCV編碼的非結(jié)構(gòu)蛋白4B(non-structuralprotein4B,NS4B)能夠直接與STING結(jié)合削弱了STING和TBK1之間的相互作用,阻斷干擾素信號的轉(zhuǎn)導(dǎo)

.另有研究顯示在機(jī)體受到外來刺激時(shí),內(nèi)質(zhì)網(wǎng)局部的STING可以移位到細(xì)胞質(zhì)并與TBK1結(jié)合,這時(shí)NS4B蛋白可能在內(nèi)質(zhì)網(wǎng)保留STING,從而抑制STING與TBK1的相互作用

.NS4B還可能通過競爭性地與STING結(jié)合干擾線粒體抗病毒信號蛋白(mitochondrial antiviral signaling protein,MAVS),阻斷STING和MAVS之間的相互作用,強(qiáng)烈抑制MAVS介導(dǎo)的IRF-3的磷酸化.綜上所述,cGAS-STING信號通路與HBV及HCV之間有著密切關(guān)聯(lián),靶向cGAS-STING信號通路可能是增強(qiáng)宿主對HBV及HCV免疫應(yīng)答的一種治療選擇.

1.2.2 觀察指標(biāo) 所有患者分別在基線及治療12個月，禁食12 h后清晨空腹抽取靜脈血5 mL，2 h內(nèi)以3 500轉(zhuǎn)速分離血清，于本院檢驗(yàn)科行生化全套及PSA等檢查，檢測總?cè)８视?TG)、總膽固醇(TC)、

想要避免一味比較的習(xí)慣，真正有效的辦法不是禁止做某事，而是用做另一件事來替代。如果我們要減少有害的比較，就得讓自己去做有益的比較。

2.2 cGAS-STING信號通路與酒精性肝病 ALD造成肝硬化的死亡率占肝硬化相關(guān)疾病的50%,ALD的病因和發(fā)病機(jī)制復(fù)雜,目前先天免疫功能障礙和過度炎癥反應(yīng)已被證實(shí)是ALD發(fā)生的重要原因之一

,對ALD患者肝細(xì)胞的基因分析結(jié)果顯示,cGAS-STING通路的激活水平與ALD的嚴(yán)重程度相關(guān).cGAS可通過連接蛋白(主要是Cx32)組成的細(xì)胞間通道驅(qū)動肝細(xì)胞和非實(shí)質(zhì)細(xì)胞中IRF3的激活

,IRF3的激活可引起酒精誘導(dǎo)的肝細(xì)胞細(xì)胞凋亡,繼而促進(jìn)炎癥反應(yīng),導(dǎo)致ALD的發(fā)生.因此,cGAS和Cx32是ALD發(fā)病機(jī)制的關(guān)鍵,可作為潛在的ALD治療靶點(diǎn).

2.4 cGAS-STING信號通路與肝癌 病毒性肝炎,如HBV、HCV是HCC發(fā)生的重要原因,此外還有過度飲酒、脂肪肝等.目前,現(xiàn)代醫(yī)學(xué)治療肝癌方式主要包括手術(shù)切除、射頻消融術(shù)、肝動脈栓塞化療術(shù)及放化療等,但臨床療效有限,預(yù)后較差,嚴(yán)重影響了患者的生存質(zhì)量

.近年來,發(fā)現(xiàn)cGAS-STING在抗腫瘤免疫反應(yīng)中起著積極的作用,其與HCC的發(fā)生發(fā)展也密切相關(guān).有報(bào)道顯示,在一定的條件下,癌細(xì)胞的細(xì)胞核和線粒體DNA會以多種形式泄漏到胞質(zhì)中,cGAS-STING信號通路被激活,促進(jìn)IFN-Ⅰ的釋放,IFN-Ⅰ的產(chǎn)生增強(qiáng)了宿主抵抗腫瘤細(xì)胞的能力.同時(shí),IFN-Ⅰ對樹突狀細(xì)胞(dendritic cells,DCs)的成熟至關(guān)重要

,DCs中cGASSTING信號可以通過吞噬死亡或受損的癌細(xì)胞、外泌體轉(zhuǎn)移和cGAMP連接被激活,然后,DCs在IFN-Ⅰ的誘導(dǎo)下遷移到腫瘤組織,激活腫瘤特異性CD8+T細(xì)胞,從而誘導(dǎo)全身抗腫瘤免疫來控制局部和遠(yuǎn)處的腫瘤生長

.此外,癌細(xì)胞中cGAS-STING信號通路的激活也會招募免疫細(xì)胞清除癌細(xì)胞,例如增強(qiáng)癌細(xì)胞對自然殺傷細(xì)胞(natural killer cells,NKs)和細(xì)胞毒性T淋巴細(xì)胞(cytotoxic T lymphocyte,CTL)的免疫攻擊的敏感性

.同時(shí),基于對多個數(shù)據(jù)庫的分析,確定了cGAS-STING通路的關(guān)鍵基因與人類樣本的HCC表型之間的聯(lián)系,發(fā)現(xiàn)絲氨酸-蘇氨酸激酶PI3家族成員ATR和ATM是HCC中潛在的激酶靶點(diǎn),ATR抑制劑增強(qiáng)了肝癌放療的抗腫瘤活性,并且可激活胞質(zhì)中cGAS-STING通路

.

2.3 cGAS-STING信號通路與非酒精性脂肪性肝病NAFLD已成為全球最主要的慢性肝病之一

,是當(dāng)下研究的熱點(diǎn),但同時(shí),其預(yù)防和治療也存在諸多難點(diǎn),目前尚無批準(zhǔn)上市的特異性藥物

.NAFLD常發(fā)生于肥胖人群和代謝綜合征患者,主要以肝細(xì)胞內(nèi)脂肪過度沉積為主要特征,病程包括單純性脂肪肝、非酒精性脂肪性肝炎和NASH相關(guān)肝硬化

.有研究表明,在高脂肪飲食(high fatty diet,HFD)的小鼠模型中,STING參與了糖脂代謝過程,喂養(yǎng)高果糖而不表達(dá)STING的小鼠表現(xiàn)出肝臟脂肪、炎癥及纖維化的減少,這表明STING的激活可能促進(jìn)了肝臟脂肪及炎癥的生成

.此外,STINGIRF3軸參與了NAFLD和早期ALD中凋亡通路的激活,STING-IRF3軸可通過與線粒體上相關(guān)蛋白Bcl-2、Bax相互作用,激活線粒體凋亡通路,造成肝細(xì)胞凋亡,上調(diào)炎癥通路

.另有研究發(fā)現(xiàn)單核細(xì)胞源性巨噬細(xì)胞和肝臟KCs中STING的激活促進(jìn)了TBK1、c-Jun氨基末端激酶(c-Jun-N-terminal kinase,JNK)和NF-kB的磷酸化

,導(dǎo)致轉(zhuǎn)化生長因子α(transforming growth factor-α,TGF-α)和白介素1β(interleukin-1β,IL-1β)生成,這些細(xì)胞因子的產(chǎn)生觸發(fā)肝細(xì)胞炎癥通路,并產(chǎn)生轉(zhuǎn)化生長因子β1(transforming growth factor β1,TGF-β1),誘導(dǎo)肝星狀細(xì)胞(hepatic stellate cells,HSCs)的激活,造成脂肪沉積和纖維化,最終驅(qū)動NAFLD發(fā)生

,甚至進(jìn)一步發(fā)生肝硬化和HCC.

2.5 cGAS-STING信號通路其他肝臟疾病 綜上所述,cGAS-STING也可能參與其他肝臟疾病發(fā)生發(fā)展過程,如肝纖維化、自身免疫性肝病和肝損傷

.有報(bào)道顯示,在NAFLD患者中,STING表達(dá)水平與肝纖維化程度呈正相關(guān),巨噬細(xì)胞中STING激活誘導(dǎo)TGF-b1釋放,從而刺激肝星狀細(xì)胞活化而導(dǎo)致纖維化.關(guān)于cGASSTING信號轉(zhuǎn)導(dǎo)和其他原因引起的肝纖維化的研究報(bào)道尚未出現(xiàn).因此,cGAS-STING信號通路參與肝纖維化發(fā)生和逆轉(zhuǎn)的機(jī)制也需要進(jìn)一步的研究.基于cGASSTING信號通路在固有免疫和適應(yīng)性免疫調(diào)節(jié)過程中的重要性,cGAS-STING信號通路可能與自身免疫性肝病密切相關(guān).近年來,cGAS和STING被發(fā)現(xiàn)參與肝臟酒精、輻射和缺血/再灌注(ischemia/reperfusion injury,IRI)等肝損傷相關(guān)進(jìn)程

.有研究證明

,酒精喂養(yǎng)的小鼠體內(nèi)表現(xiàn)出cGAS-STING信號水平的升高,這是因?yàn)榫凭碳な沟脙?nèi)質(zhì)網(wǎng)(endoplasmic reticulum,ER)應(yīng)激引發(fā)cGAS-STING通路激活和IRF3磷酸化,進(jìn)而導(dǎo)致肝細(xì)胞凋亡并伴有早期肝纖維化,而cGAS驅(qū)動的IRF3激活是通過肝細(xì)胞間的縫隙連接傳遞實(shí)現(xiàn)的,這個過程可加重肝損傷的程度.另一項(xiàng)研究報(bào)告稱

,cGAS敲除小鼠在IRI反應(yīng)中表現(xiàn)出更嚴(yán)重的肝損傷,而被STING siRNA轉(zhuǎn)染的小鼠表現(xiàn)出更低水平的肝損傷

.還有報(bào)道將IRI的改善歸因于cGAS對肝細(xì)胞自噬的誘導(dǎo)

.總的來說,cGAS-STING信號通路激活加劇炎癥和組織損傷的證據(jù)目前是充分的,但仍然需要進(jìn)一步研究cGAS是通過經(jīng)典細(xì)胞因子的產(chǎn)生加重組織損傷,還是通過自噬減輕組織損傷,以及哪種作用占主導(dǎo)地位.

3 cGAS-STING信號通路臨床應(yīng)用進(jìn)展

如前所述,激活cGAS-STING信號通路對肝病毒感染和腫瘤具有顯著的抑制作用,因此成為近年來肝病免疫學(xué)和腫瘤學(xué)領(lǐng)域的熱門靶點(diǎn).目前,研究的重點(diǎn)主要集中在蛋白水平的臨床應(yīng)用靶向藥物,包括STING激動劑和抑制劑.在基因水平上的治療研究進(jìn)展主要集中在肝炎病毒,特別是HBV感染.有臨床研究報(bào)道稱cGAS-STING信號通路在肝癌放療免疫應(yīng)答的過程中發(fā)揮關(guān)鍵作用,放療誘導(dǎo)的外源DNA損傷可作為胞質(zhì)DNA激活cGASSTING信號通路,誘導(dǎo)產(chǎn)生IFN-Ⅰ,促進(jìn)放療效果

.此外,cGAS-STING信號通路激動劑還可以與免疫檢查點(diǎn)阻斷劑治療、CAR-T治療、溶瘤病毒治療等聯(lián)合使用

.當(dāng)然,最常見的臨床應(yīng)用研究是STING激動劑作為癌癥疫苗佐劑

,適當(dāng)?shù)氖褂每稍诳朔庖吣褪芎驮鰪?qiáng)腫瘤特異性免疫中起著重要作用.

1．1 一般資料 對2006－2011年在如東縣接受兒童系統(tǒng)管理的27 662例3個月內(nèi)小嬰兒聽力篩查資料進(jìn)行調(diào)查分析。

4 結(jié)論和展望

綜上所述,越來越多的證據(jù)表明cGAS-STING信號通路在多種肝臟疾病的發(fā)病機(jī)制中發(fā)揮重要作用.在乙型病毒性肝炎和HCC中,cGAS-STING信號通路抑制疾病進(jìn)展,激活該通路可顯著提高治療效果.而在ALD和NAFLD中該通路起促進(jìn)疾病進(jìn)展的作用.作為新發(fā)現(xiàn)的通路,cGAS-STING具有廣闊的臨床應(yīng)用前景,是治療研究的一個重要潛在方向,如何用好這把“雙刃劍”是我們要思考的問題.

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