炎性小體激活與細(xì)胞焦亡的研究進(jìn)展

楊斯迪，鄧奇峰，黃瑞，吳淑燕

蘇州大學(xué)醫(yī)學(xué)部基礎(chǔ)醫(yī)學(xué)與生物科學(xué)學(xué)院，蘇州 215123

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·綜述·

炎性小體激活與細(xì)胞焦亡的研究進(jìn)展

楊斯迪，鄧奇峰，黃瑞，吳淑燕

蘇州大學(xué)醫(yī)學(xué)部基礎(chǔ)醫(yī)學(xué)與生物科學(xué)學(xué)院，蘇州 215123

細(xì)胞焦亡是一種依賴天冬氨酸特異性半胱氨酸蛋白酶1(cysteinyl aspartate specific proteinase 1，caspase-1)/caspase-11的程序性細(xì)胞死亡方式。炎性小體的激活在細(xì)胞焦亡過(guò)程中扮演重要角色。當(dāng)病原體入侵時(shí)，核苷酸結(jié)合寡聚化結(jié)構(gòu)域樣受體(nucleotide-binding oligomerization domain-like receptor，NLR)和黑色素瘤缺乏因子2(absent in melanoma 2，AIM2)等胞內(nèi)模式識(shí)別受體(pattern recognition receptor，PRR)與相應(yīng)配體結(jié)合，導(dǎo)致炎性小體多蛋白復(fù)合物組裝和caspase-1/caspase-11激活，進(jìn)而誘導(dǎo)細(xì)胞焦亡發(fā)生。深入研究炎性小體激活和細(xì)胞焦亡的相關(guān)機(jī)制，對(duì)認(rèn)識(shí)炎癥性疾病的發(fā)生發(fā)展非常重要。本文就炎性小體激活與細(xì)胞焦亡的研究進(jìn)展進(jìn)行綜述。

細(xì)胞焦亡；炎性小體；Caspase-1；Caspase-11

2001年，Brennan和Cookson[1]在沙門菌(Salmonellaspp.)感染巨噬細(xì)胞模型中發(fā)現(xiàn)一種有別于細(xì)胞凋亡且依賴天冬氨酸特異性半胱氨酸蛋白酶1(cysteinyl aspartate specific proteinase 1，caspase-1)的細(xì)胞程序性死亡方式，稱為“細(xì)胞焦亡”(pyroptosis)。焦亡是以細(xì)胞腫脹裂解、細(xì)胞膜溶解(胞質(zhì)內(nèi)容物釋放到細(xì)胞外)為主要特征的細(xì)胞炎性死亡，是宿主抵抗胞內(nèi)病原體感染的天然免疫防御機(jī)制之一[2]。當(dāng)細(xì)菌和病毒等內(nèi)源性或外源性危險(xiǎn)信號(hào)刺激機(jī)體時(shí)，細(xì)胞內(nèi)的模式識(shí)別受體(pattern recognition receptor，PRR)通過(guò)識(shí)別病原體相關(guān)分子模式(pathogen-associated molecular pattern，PAMP)和損傷相關(guān)分子模式(damage-associated molecular pattern，DAMP)，啟動(dòng)一系列信號(hào)級(jí)聯(lián)反應(yīng)以活化caspase-1前體，誘導(dǎo)細(xì)胞焦亡發(fā)生，進(jìn)而釋放大量促炎細(xì)胞因子，如白細(xì)胞介素1β(interleukin 1β，IL-1β)和IL-18。促炎信號(hào)的產(chǎn)生可將更多免疫細(xì)胞募集至感染病灶，在擴(kuò)大炎癥反應(yīng)的同時(shí)，胞內(nèi)病原菌由于失去細(xì)胞保護(hù)而更易被吞噬細(xì)胞殺滅[3]。

炎性小體是由PRR參與組裝的多蛋白復(fù)合物，可識(shí)別PAMP或宿主來(lái)源的DAMP，進(jìn)而激活caspase-1。目前研究較多的4種炎性小體——NLRP1〔nucleotide-binding oligomerization domain (NOD)-like receptor family, pyrin domain containing 1〕、NLRP3、NLRC4〔NOD-like receptor family, caspase recruitment domain (CARD) containing 4〕和黑色素瘤缺乏因子2(absent in melanoma 2，AIM2)均可通過(guò)經(jīng)典途徑介導(dǎo)炎性小體多蛋白復(fù)合物的組裝，從而促進(jìn)caspase-1前體自我切割產(chǎn)生caspase-1，后者進(jìn)一步將IL-1β前體和IL-18 前體剪切成具有生物學(xué)活性的IL-1β和IL-18[4]。此外，caspase-11作為內(nèi)源性脂多糖(lipopolysaccharide，LPS)受體，還可通過(guò)不依賴caspase-1活化的非經(jīng)典途徑介導(dǎo)IL-1β和IL-18的修飾和釋放[5]。細(xì)胞焦亡和炎性小體對(duì)IL-1β前體和IL-18前體的剪切修飾均依賴caspase-1/caspase-11。隨著研究的深入，科學(xué)家們發(fā)現(xiàn)炎性小體在調(diào)控細(xì)胞焦亡和凋亡等多種細(xì)胞死亡模式中發(fā)揮重要作用[6]。

1 細(xì)胞焦亡的發(fā)生途徑

1.1 依賴caspase-1的經(jīng)典細(xì)胞焦亡途經(jīng)

Caspase家族中多種半胱天冬酶引發(fā)的級(jí)聯(lián)反應(yīng)是調(diào)控細(xì)胞死亡方式的中心環(huán)節(jié)，其中caspase-3是細(xì)胞凋亡的主要調(diào)控因子，而caspase-1/ caspase-11依賴的細(xì)胞炎性死亡則主要介導(dǎo)細(xì)胞焦亡[7]。當(dāng)病原體入侵時(shí)，核苷酸結(jié)合寡聚化結(jié)構(gòu)域樣受體(nucleotide-binding oligomerization domain-like receptor，NLR)、細(xì)胞質(zhì)DNA傳感器AIM2等胞內(nèi)主要PRR可與相應(yīng)配體結(jié)合，引起炎性小體多蛋白復(fù)合物組裝和caspase-1激活，導(dǎo)致細(xì)胞膜上形成質(zhì)膜孔，進(jìn)而發(fā)生細(xì)胞滲透性腫脹破裂。此過(guò)程伴隨著IL-1β、IL-18和高遷移率族蛋白B1(high mobility group box 1，HMGB1)等大量炎癥因子釋放，最終放大局部炎癥反應(yīng)，這是細(xì)胞焦亡發(fā)生的重要機(jī)制[7-9]。在沙門菌感染巨噬細(xì)胞模型中，人們首次發(fā)現(xiàn)了caspase-1介導(dǎo)的細(xì)胞死亡方式[10]。此后研究發(fā)現(xiàn)，除PAMP可誘導(dǎo)細(xì)胞焦亡外，DAMP和活性氧(reactive oxygen species，ROS)亦可引起caspase-1依賴的細(xì)胞炎性死亡[11]。但此過(guò)程中細(xì)胞焦亡是否受caspase-1本身或其他介質(zhì)如caspase-11的調(diào)控，尚未明確。

1.2 非caspase-1依賴的細(xì)胞焦亡途經(jīng)

與caspase-1不同，caspase-11在鼠源巨噬細(xì)胞中僅與胞內(nèi)LPS特異性結(jié)合，并在Toll樣受體4(Toll-like receptor 4，TLR4)和caspase-1非依賴的細(xì)胞死亡過(guò)程中發(fā)揮重要作用[12-13]。大腸埃希菌(Escherichiacoli，E.coli)、鼠傷寒沙門菌(Salmonellatyphimurium，S.typhimurium)和福氏志賀菌(Shigellaflexneri，S.flexneri)等多種革蘭陰性菌的LPS均可激活caspase-11，進(jìn)而誘導(dǎo)細(xì)胞焦亡發(fā)生和IL-1β分泌[14]，但caspase-11在上述下游信號(hào)事件中的確切機(jī)制尚待進(jìn)一步闡明。研究顯示，革蘭陰性菌LPS可通過(guò)激活TRIF(TIR-domain-containing adapter-inducing interferon β)信號(hào)通路介導(dǎo)β干擾素(interferon β，IFN-β)釋放，IFN-β通過(guò)自分泌/旁分泌的方式調(diào)控caspase-11表達(dá)，從而啟動(dòng)caspase-11依賴的細(xì)胞焦亡[15-16]。在此過(guò)程中，caspase-11可剪切并激活小鼠中保守的Gsdmd基因產(chǎn)物Gasdermin D，而Gasdermin D經(jīng)剪切產(chǎn)生的N端p30片段可促使細(xì)胞膜表面質(zhì)膜孔形成和細(xì)胞腫脹破裂，是啟動(dòng)細(xì)胞焦亡的關(guān)鍵[17-18]。Yang等[19]最近發(fā)現(xiàn)縫隙連接蛋白pannexin-1是介導(dǎo)caspase-11非經(jīng)典途徑細(xì)胞焦亡中的另一關(guān)鍵蛋白。內(nèi)源性LPS與caspase-11特異性結(jié)合后，激活的caspase-11可剪切修飾跨膜通道pannexin-1，引起細(xì)胞ATP釋放，從而誘導(dǎo)離子通道P2X7受體依賴性細(xì)胞焦亡[20]。

感知內(nèi)源性LPS后，誘導(dǎo)caspase-11依賴的細(xì)胞焦亡是小鼠天然免疫的重要環(huán)節(jié)，但目前尚不清楚該途徑是否在人類中起作用。研究表明，人類caspase-4 和caspase-5是caspase-11的同源類似物。在人單核細(xì)胞中，內(nèi)源性LPS誘導(dǎo)的焦亡依賴高水平caspase-4表達(dá)；caspase-4和caspase-11的功能可在某些小鼠或人類細(xì)胞中相互替代。但與小鼠細(xì)胞識(shí)別內(nèi)源性LPS不同，人類細(xì)胞主要通過(guò)TLR4/MD2復(fù)合物識(shí)別LPS，LPS與caspase-4/caspase-11高親和力結(jié)合后可誘導(dǎo)caspase-4/caspase-11寡聚化并激活相應(yīng)信號(hào)級(jí)聯(lián)反應(yīng)，最終導(dǎo)致細(xì)胞焦亡。因此，caspase-4/caspase-5/caspase-11可作為內(nèi)源性LPS的天然受體，在革蘭陰性菌入侵宿主細(xì)胞過(guò)程中扮演重要角色。

2 細(xì)胞焦亡與炎性小體的關(guān)系

2.1 NLRP1通過(guò)識(shí)別炭疽致死毒素(lethal toxin，LeTx)誘導(dǎo)細(xì)胞焦亡

首先被報(bào)道的炎性小體是NLRP1[21]。人類NLRP1是目前發(fā)現(xiàn)的唯一含有pyrin和CARD結(jié)構(gòu)域的NLR。在NLRP1炎性體形成過(guò)程中，NLRP1可不依賴凋亡相關(guān)斑點(diǎn)樣蛋白(apoptosis-associated speck-like protein containing a CARD，ASC)，而是直接通過(guò)CARD-CARD相互作用募集caspase-1前體，介導(dǎo)caspase-1激活后致細(xì)胞焦亡發(fā)生。NLRP1基因的表達(dá)呈多樣性，人源性和大部分靈長(zhǎng)類動(dòng)物NLRP1基因只表達(dá)NLRP1，而鼠源性NLRP1基因則表達(dá)3種同系物NLRP1a、NLRP1b和NLRP1c，其中NLRP1b是小鼠巨噬細(xì)胞識(shí)別LeTx的重要PRR。Boyden等[22]發(fā)現(xiàn)，NLRP1b識(shí)別LeTx后可進(jìn)一步活化caspase-1，從而誘導(dǎo)細(xì)胞焦亡發(fā)生，在此過(guò)程中ASC并不參與LeTx誘導(dǎo)的細(xì)胞焦亡和IL-1β釋放[23]。NLRP1b在不同小鼠品系中呈現(xiàn)基因多態(tài)性，如B6遺傳背景小鼠雖然能表達(dá)NLRP1a/b，但不識(shí)別LeTx[24]。進(jìn)一步研究表明，LeTx中致死因子(lethal factor，LF)失活可導(dǎo)致NLRP1b和caspase-1依賴的細(xì)胞焦亡缺失[25]。除LeTx外，研究人員在剛地弓形蟲(Toxoplasmagondii)感染的大鼠巨噬細(xì)胞中發(fā)現(xiàn)NLRP1表達(dá)水平升高，NLRP1炎性小體激活，細(xì)胞焦亡發(fā)生[26]。此外，NLRP1表達(dá)水平降低可抑制人單核細(xì)胞系THP-1細(xì)胞焦亡[27]，表明NLRP1在宿主抵抗剛地弓形蟲感染過(guò)程中發(fā)揮重要作用。

2.2 NLRP3識(shí)別多種配體誘導(dǎo)細(xì)胞焦亡

NLRP3由NLRP3蛋白、接頭蛋白ASC及caspase-1前體組成，是目前結(jié)構(gòu)和功能最為明確的炎性小體。NLRP3可被細(xì)菌、病毒、二氧化硅和石棉等多種內(nèi)源性或外源性因素激活[28]。接受活化信號(hào)刺激后，ASC可通過(guò)CARD-CARD和PYD-PYD結(jié)構(gòu)域相互作用的方式分別募集NLRP3和caspase-1前體，從而介導(dǎo)caspase-1激活及促炎因子釋放，導(dǎo)致細(xì)胞焦亡發(fā)生。經(jīng)典的NLRP3激活過(guò)程分為兩個(gè)階段，即TLR4信號(hào)通路介導(dǎo)的NLRP3和IL-1β前體轉(zhuǎn)錄水平升高的預(yù)激活階段，以及NLRP3轉(zhuǎn)錄后修飾激活的第二階段[29]。非經(jīng)典的NLRP3激活途徑不依賴TLR4信號(hào)的預(yù)激活，由caspase-11直接識(shí)別LPS。雖然NLRP3調(diào)控細(xì)胞焦亡的機(jī)制還不明確，但近期發(fā)現(xiàn)caspase-11可將Gasdermin D蛋白切割成兩部分，其中相對(duì)分子質(zhì)量為22 000的C端片段功能未知，但相對(duì)分子質(zhì)量為31 000的N端片段則是啟動(dòng)細(xì)胞焦亡的關(guān)鍵。在此過(guò)程中，NLRP3一方面在宿主免疫防御過(guò)程中發(fā)揮重要作用；另一方面，過(guò)度炎癥反應(yīng)及細(xì)胞焦亡的發(fā)生可對(duì)機(jī)體造成不可逆損傷[17,30]。骨髓增生異常綜合征(myelodysplastic syndrome，MDS)和老年性黃斑退化癥(age-related macular degeneration，AMD)等多種疾病與NLRP3介導(dǎo)的細(xì)胞焦亡密切相關(guān)。此外，β淀粉樣蛋白可通過(guò)激活NLRP3繼而引發(fā)caspase-1依賴的細(xì)胞焦亡，表明阿爾茲海默癥的發(fā)生發(fā)展與NLRP3的激活相關(guān)[31]。

2.3 NLRC4通過(guò)識(shí)別鞭毛蛋白和Ⅲ型分泌系統(tǒng)基座蛋白PrgJ誘導(dǎo)細(xì)胞焦亡

NLRC4也稱為IPAF，主要參與機(jī)體抵抗革蘭陰性菌為主的病原菌感染過(guò)程。2004年，Mariathasan等首次報(bào)道了NLRC4在沙門菌感染中的重要作用[32]。隨后，NLRC4在機(jī)體抵抗嗜肺軍團(tuán)菌(Legionellapneumophila，L.pneumophila)、銅綠假單胞菌(Pseudomonasaeruginosa，P.aeruginosa)、福氏志賀菌等病原體感染中的作用也相繼被發(fā)現(xiàn)。NLRC4由N端CARD結(jié)構(gòu)域、中間NOD結(jié)構(gòu)域和C端LRR結(jié)構(gòu)域3部分組成。雖然NLRC4本身N端具有CARD結(jié)構(gòu)域，但與NLRP1不同，接頭蛋白ASC在NLRC4募集caspase-1介導(dǎo)的細(xì)胞焦亡過(guò)程中仍具有重要作用。嗜肺軍團(tuán)菌和銅綠假單胞菌鞭毛蛋白(flagellin)突變株不能誘導(dǎo)NLRC4多蛋白復(fù)合物的組裝，因此不能啟動(dòng)caspase-1依賴的IL-1β釋放和細(xì)胞焦亡，表明病原菌能否激活NLRC4取決于該菌是否表達(dá)單體鞭毛蛋白[33-34]。除鞭毛蛋白外，細(xì)菌Ⅲ型分泌系統(tǒng)基座蛋白PrgJ亦可激活NLRC4，引發(fā)下游信號(hào)級(jí)聯(lián)反應(yīng)[35-36]。最新研究發(fā)現(xiàn)，沙門菌感染巨噬細(xì)胞時(shí)，活化的NLRC4可招募NLRP3，進(jìn)而激活caspase-1，啟動(dòng)細(xì)胞焦亡[37]。因此，在機(jī)體抗感染免疫中各炎性小體相互作用可作為細(xì)胞焦亡的共同調(diào)控因子。

2.4 AIM2通過(guò)識(shí)別雙鏈DNA誘導(dǎo)細(xì)胞焦亡

AIM2屬于HIN-200家族，主要在細(xì)胞質(zhì)中表達(dá)，由N端的PYD結(jié)構(gòu)域和C端的HIN結(jié)構(gòu)域組成。通過(guò)HIN結(jié)構(gòu)域，AIM2可直接結(jié)合多種病毒DNA和細(xì)菌雙鏈DNA[38]。當(dāng)病原體入侵后，AIM2可經(jīng)接頭蛋白ASC活化caspase-1，導(dǎo)致IL-1β和IL-18的成熟和釋放以及細(xì)胞焦亡的發(fā)生。AIM2缺陷的巨噬細(xì)胞在牛痘病毒和巨細(xì)胞病毒感染時(shí)均不能有效激活caspase-1[39]。而進(jìn)入巨噬細(xì)胞的土拉弗朗西斯菌(Francisellatularensis，F(xiàn).tularensis)可被AIM2識(shí)別并結(jié)合，隨后活化的caspase-1刺激Ⅰ型干擾素IFN-α與IFN-β釋放，最終導(dǎo)致細(xì)胞焦亡[40]。產(chǎn)單核細(xì)胞李斯特菌(Listeriamonocytogenes，L.monocytogenes)感染細(xì)胞模型中也有類似現(xiàn)象[41]，但AIM2調(diào)控細(xì)胞焦亡的相關(guān)機(jī)制尚未完全明了。

3 結(jié)語(yǔ)

細(xì)胞焦亡是一種以細(xì)胞腫脹裂解、細(xì)胞膜溶解和大量促炎因子釋放為主要表現(xiàn)形式的程序性細(xì)胞死亡方式，常伴隨炎性小體和caspase-1/caspase-11的激活。盡管近年來(lái)關(guān)于兩者間關(guān)系的分子機(jī)制不斷有新發(fā)現(xiàn)，但尚存在眾多未解之謎。細(xì)胞焦亡在炎性小體相關(guān)宿主抗感染免疫過(guò)程中是一把“雙刃劍”：一方面，細(xì)胞焦亡的發(fā)生有助于病原體的清除，防止感染；另一方面，過(guò)度的caspase-1激活可導(dǎo)致病理性炎癥反應(yīng)。此外，編碼NLR蛋白的基因突變會(huì)導(dǎo)致異常的caspase-1激活，從而引起自身免疫性疾病。作為新定義的一種細(xì)胞死亡類型，焦亡表現(xiàn)出與病原體的特定關(guān)系，且與眾多自身免疫性疾病、炎癥性疾病的發(fā)生發(fā)展密切相關(guān)。深入研究炎性小體調(diào)控細(xì)胞焦亡的分子機(jī)制有助于認(rèn)識(shí)其在各類疾病中的作用，從而為治療炎癥性疾病提供新的思路和手段。

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. WU Shuyan, E-mail: shuyanzw@aliyun.com

Research progress on inflammasome activation and pyroptosis

YANG Sidi, DENG Qifeng, HUANG Rui, WU Shuyan

School of Biology & Basic Medical Sciences, Medical College of Soochow University, Suzhou 215123, China

Pyroptosis is a new form of programmed cell death depending on cysteinyl aspartate specific proteinase 1 (caspase-1). Inflammasome plays a significant role in regulating pyroptosis. Intracellular pattern recognition proteins such as nucleotide-binding oligomerization domain-like receptor (NLR) and absent in melanoma 2 (AIM2) act to their ligands and promote the assembly of inflammasome as well as the activation of caspase-1/caspase-11, then induce pyroptosis. The in-depth research on the mechanisms and correlation between pyroptosis and inflammasome contributes to the understanding of the occurrence and development of pyroptosis-related inflammatory diseases.

Pyroptosis; Inflammasome; Caspase-1; Caspase-11

吳淑燕

2016-11-22)