李克雷，李 想，叢 喆，薛 婧

(北京協(xié)和醫(yī)學(xué)院比較醫(yī)學(xué)中心，中國醫(yī)學(xué)科學(xué)院醫(yī)學(xué)實驗動物研究所，衛(wèi)生部人類疾病比較醫(yī)學(xué)重點實驗室， 國家中醫(yī)藥管理局人類疾病動物模型三級實驗室，北京 100021)

唾液酸黏附素Siglec-1在疾病中作用的研究進展

李克雷，李 想，叢 喆*，薛 婧*

(北京協(xié)和醫(yī)學(xué)院比較醫(yī)學(xué)中心，中國醫(yī)學(xué)科學(xué)院醫(yī)學(xué)實驗動物研究所，衛(wèi)生部人類疾病比較醫(yī)學(xué)重點實驗室， 國家中醫(yī)藥管理局人類疾病動物模型三級實驗室，北京 100021)

研究報告

唾液酸黏附素(Siglec-1 或 CD169)是表達(dá)于組織的巨噬細(xì)胞上免疫球蛋白超家族類黏附分子。在炎癥反應(yīng)中，Siglec-1可調(diào)節(jié)MIP-1α/β、MCP-1、MIP-2等細(xì)胞因子的分泌，促進炎癥反應(yīng)的發(fā)生；在病毒感染過程中，Siglec-1可通過介導(dǎo)病原體與巨噬細(xì)胞的的結(jié)合，促進病毒感染和吞噬；在對免疫的調(diào)節(jié)過程中，Siglec-1既可也以抑制IFN-α的過量表達(dá)，抑制固有免疫，也可抑制DC細(xì)胞活性，降低適應(yīng)性免疫。本文主要闡述了Siglec-1在病原體感染、炎癥反應(yīng)和免疫調(diào)節(jié)中最新研究進展。

Siglec-1；炎癥反應(yīng)；免疫調(diào)節(jié)；HIV

圖1 Siglecs家族成員結(jié)構(gòu)Fig.1 The structure of siglec family members

Siglecs(sialic acid-binding immunoglobulin-type lectins)是宿主最大的一組唾液酸結(jié)合蛋白，是表達(dá)于免疫系統(tǒng)的I型跨膜蛋白[1]，該蛋白的胞外區(qū)由N端與唾液酸結(jié)合的V型 Ig結(jié)構(gòu)域和不定數(shù)量的C2型結(jié)構(gòu)域組成，胞內(nèi)部分為含有賴氨酸的短尾[2]；根據(jù)序列相似性和進化上的保守性，Siglecs可分為兩類：一類是在哺乳動物上高度保守的，包括Siglec-1、CD22 (Siglec-2), MAG (myelin-associated glycoprotein) (Siglec-4) and Siglec-15；另一類是CD33相關(guān)Siglecs，在人類中這一類包括CD33、Siglecs-5、-6、-7、-8、-9、-10、-11、-14 和-16，在小鼠中這一類包括鼠的 CD33、Siglec-E、-F、-G 和 -H[3]。Siglecs中部分成員結(jié)構(gòu)比較如圖1[4]所示。

由圖中可以看出除了Siglec-1與Siglec-4外，Siglecs的其他成員的胞漿內(nèi)區(qū)域都包含兩個保守基序，該基序的類似ITIMs，這就說明Siglecs可能在免疫系統(tǒng)中調(diào)節(jié)細(xì)胞活性的功能。已有多種研究證實Sigelcs除了具有調(diào)節(jié)吸附作用外，還具有調(diào)節(jié)免疫細(xì)胞活性的功能。B細(xì)胞表達(dá)的Siglec-2可與B細(xì)胞表面受體結(jié)合形成復(fù)合物，活化的Siglec-2可活化酪氨酸磷酸酶SHP-1負(fù)調(diào)節(jié)B細(xì)胞的活性[5-7]。CD33相關(guān)的Siglecs也可活化SHP-1或SHP-2調(diào)節(jié)細(xì)胞活性，其中缺少ITIMs的Siglec-14和Siglec-16也可通過DAP12來活化或抑制細(xì)胞信號的傳導(dǎo)[8-10]。

Siglec-1，也被稱作CD169、sialoadhesin (Sn)，主要表達(dá)與單核巨噬細(xì)胞和樹突狀細(xì)胞表面，大小約為185KD，其胞外區(qū)域有17個免疫球蛋白樣結(jié)構(gòu)域組成[11]。早期的研究發(fā)現(xiàn)Siglec-1不僅可介導(dǎo)細(xì)胞間吸附[12,13]，還能夠促進炎癥反應(yīng)的發(fā)生。Siglec-1作為第一個被發(fā)現(xiàn)的Siglecs成員[14]，對其功能的研究，尤其是在病原體感染時，Siglec-1在免疫系統(tǒng)中的作用仍不是很清楚。那么，本文就Siglec-1病原體感染中的作用做一綜述，為對Siglec-1的進一步研究提供思路。

1 Siglec-1的表達(dá)和調(diào)節(jié)

Siglec-1 組成性表達(dá)于特定組織巨噬細(xì)胞上[15]，IFN-α和能夠引發(fā)I型IFN反應(yīng)的分子比，如LPS和poly I:C，是誘導(dǎo)Siglec-1表達(dá)的重要因子[16]。當(dāng)機體收受到炎癥刺激時，單核細(xì)胞被激活，單核巨噬細(xì)胞細(xì)胞表面的Siglec-1的表達(dá)量迅速升高，參與單核巨噬細(xì)胞介導(dǎo)的促炎癥反應(yīng)，并發(fā)揮作用。

在冠心病的發(fā)病過程中，Siglec-1蛋白及mRNA在冠心病患者外周血單核細(xì)胞上的表達(dá)量顯著升高， Siglec-1通過促進MIP-1α/β、MCP-1、MIP-2分泌加速炎癥反應(yīng)的發(fā)生[17]；在某些炎癥性疾病中， 病變組織巨噬細(xì)胞和外周血單核細(xì)胞都表現(xiàn)為Siglec-1 表達(dá)上調(diào)，并與疾病進程有一定相關(guān)性。在人類腎炎患者中，Siglec-1主要表達(dá)在腎小球和腎間質(zhì)，Siglec-1 表達(dá)與蛋白尿水平及腎臟損傷呈正相關(guān)，且腎間質(zhì)中Siglec-1 陽性細(xì)胞表達(dá)與 CD3+T 細(xì)胞呈正相關(guān)；激素治療后，大部分患者蛋白尿和腎小球損傷得到緩解，腎小球中 Siglec-1 陽性巨噬細(xì)胞數(shù)量也減少[18]。Siglec-1還可調(diào)節(jié)自身的免疫應(yīng)答。正常情況下，敲除Siglec-1基因?qū)π∈蟮脑煅δ芎兔庖吖δ懿粫刑笥绊懀?但在 IRBP 抗原肽誘導(dǎo)的實驗性自身免疫性葡萄膜視網(wǎng)膜炎中，Siglec-1敲除小鼠的疾病發(fā)生顯著減少，T細(xì)胞的增殖能力也明顯降低，其分泌IFN-γ的水平更低，巨噬細(xì)胞產(chǎn)生NO的水平顯著降低[19]，說明Siglec-1 參與了調(diào)節(jié)自身的免疫應(yīng)答。但炎癥反應(yīng)發(fā)生時，Siglec-1對炎癥性細(xì)胞及固有免疫細(xì)胞的調(diào)節(jié)作用仍然不很清楚。

總之， 在炎癥性疾病中， 病變組織巨噬細(xì)胞和外周血單核細(xì)胞都變現(xiàn)為Siglec-1 表達(dá)上調(diào)， 并與疾病進程有一定相關(guān)性，經(jīng)藥物治療后，Siglec-1表達(dá)也隨之下調(diào)。Siglec-1在炎癥反應(yīng)中的具體作用仍不清楚，但動態(tài)監(jiān)測 Siglec-1 可用于對疾病的評估和療效觀察。

2 Siglec-1的作用

2.1 介導(dǎo)吞噬作用

Siglec-1通過與自身抗原的結(jié)合介導(dǎo)巨噬細(xì)胞對自身抗原的吞噬，降低自身免疫疾病的發(fā)生。在淋巴結(jié)中，Siglec-1組成性表達(dá)于含有內(nèi)吞小泡的囊下竇巨噬細(xì)胞中[20]，說明Siglec-1可能具有介導(dǎo)胞吞的作用。隨后的研究證實，巨噬細(xì)胞可通過依賴Siglec-1的方式攝取腦膜炎奈瑟氏菌[21]，并且Siglec-1可通過與病毒膜蛋白上的唾液酸結(jié)合，介導(dǎo)巨噬細(xì)胞對病毒的吞噬作用的[22,23]。因此，在病原體或其他表達(dá)的Siglec-1配體物質(zhì)入侵機制是，表達(dá)有Siglec-1巨噬細(xì)胞可特異性發(fā)揮吞噬作用。

2.2 介導(dǎo)巨噬細(xì)胞的抗原呈遞作用

Siglec-1表達(dá)分布主要在脾臟中邊緣區(qū)嗜金屬巨噬細(xì)胞和濾泡旁區(qū)的巨噬細(xì)胞及淋巴結(jié)中的囊下竇和髓索內(nèi)的巨噬細(xì)胞[24]，由于這類巨噬細(xì)胞的位置與血液和淋巴液相關(guān)，說明Siglec-1可能在機體對血液和淋巴液中病原或自身的抗原的免疫反應(yīng)中發(fā)揮重要作用。

脾臟邊緣區(qū)巨噬細(xì)胞可與CD8+DC共同激活細(xì)胞毒性T細(xì)胞[25]，在這一過程中，表達(dá)Siglec-1的巨噬細(xì)胞可將抗原大量轉(zhuǎn)移給CD8+DC，最終DC可有效的通過交叉遞呈，將抗原呈遞給T細(xì)胞，活化細(xì)胞毒性T細(xì)胞。Siglec-1可能在巨噬細(xì)胞和DC的相互作用中發(fā)揮作用。淋巴結(jié)中的囊下竇巨噬細(xì)胞從血液中捕獲抗原后可直接作為抗原呈遞細(xì)胞將抗原呈遞給B細(xì)胞，然后B細(xì)胞將抗原運送至生發(fā)中心，引發(fā)免疫反應(yīng)[26]。由于囊下竇巨噬細(xì)胞高表達(dá)Siglec-1,是否Siglec-1介導(dǎo)了這一過程需要進一步的研究證實。

表達(dá)Siglec-1的巨噬細(xì)胞可通過將死亡的腫瘤抗原交叉呈遞給CD8+T細(xì)胞活化抗腫瘤免疫反應(yīng)[27[28]，用IFN-α處理豬來源的單核細(xì)胞或單核來源的DC后，Siglec-1抗體可在低濃度誘導(dǎo)T細(xì)胞活化，這就說明Siglec-1可增強抗原Siglec-1配體與MHC的結(jié)合，并促進抗原遞呈作用。

2.3 抑制免疫應(yīng)答

與Sigelcs其他成員的功能類似，Siglec-1也可負(fù)調(diào)節(jié)細(xì)胞活性，有研究表明在鼻病毒感染的時候，Siglec-1在DC細(xì)胞上的表達(dá)也可降低DC的抗原遞呈作用而降低適應(yīng)性免疫應(yīng)答[29]。這一過程主要是通過誘導(dǎo)DC表達(dá)Siglec-1和B7-H1從而使DC細(xì)胞分泌IL-35，IL-35通過誘導(dǎo)Treg細(xì)胞而發(fā)揮抑制適應(yīng)性免疫應(yīng)答的作用[30]。對固有免疫的抑制作用主要表現(xiàn)在對I型IFN表達(dá)的抑制。HSV等病毒感染巨噬細(xì)胞可通過IFN-JAK-STAT1途徑誘導(dǎo)Siglec-1表達(dá)升高，Siglec-1可通過TRIM27泛素化降解TBK1，負(fù)調(diào)節(jié)IFN的過度表達(dá)，從而抑制固有免疫反應(yīng)，加強病毒的免疫逃逸[31]?？傊@些研究結(jié)果最終表明Siglec-1在病毒的感染過程中發(fā)揮了重要作用，即Siglec-1可促進病毒的感染。

2.4 促進HIV感染

Siglec-1作為凝集素家族的成員又可與多種病毒膜蛋白上的唾液酸結(jié)合，介導(dǎo)病原體的感染。Nathalie等[15]證實PRRSV在進入豬肺泡巨噬細(xì)胞過程中，Siglec-1發(fā)揮了作用，進一步研究發(fā)現(xiàn)，PRRSV病毒表面的唾液酸與Siglec-1的結(jié)合可介導(dǎo)病毒的感染[32]，即Siglec-1與α2，3唾液酸相互作用介導(dǎo)了細(xì)胞對病毒的吸附和內(nèi)化[33]，隨后的研究表明，PPRSV與巨噬細(xì)胞的結(jié)合依賴于Siglec-1的 N端免疫球蛋白樣結(jié)構(gòu)域的唾液酸結(jié)合活性[34]。Delputte等[35]證實，用IFNα誘導(dǎo)單核細(xì)胞表達(dá)Siglec-1后，可增強PRRSV對單核細(xì)胞的易感性。

在對HIV的研究中，Cornelissen等[36]發(fā)現(xiàn)在AIDS相關(guān)的Kaposi’ s sarcoma(AIDS-KS)患者體內(nèi)的組織巨噬細(xì)胞上Siglec-1表達(dá)顯著上調(diào)，隨后，有研究表明，在HIV感染時循環(huán)系統(tǒng)中的CD14+單核細(xì)胞也高表達(dá)Siglec-1，并且經(jīng)ART治療后Siglec-1表達(dá)量降低[37,38]。作為單核巨噬細(xì)胞活化的標(biāo)志，Siglec-1表達(dá)上調(diào)和下調(diào)與HIV感染有什么關(guān)呢？為了說明這一問題， van der Kuyl等[37]發(fā)現(xiàn)，在AIDS患者(AIDS-KS患者、non-AIDS-KS患者)PBMC中，Siglec-1的mRNA水平要遠(yuǎn)遠(yuǎn)高于非HIV感染的患者，并且AIDS 患者與AIDS-KS患者的PBMC中Siglec-1的mRNA水平并無顯著差異。在HIV感染早期，CD14+細(xì)胞高表達(dá)Siglec-1，并且Siglec-1的表達(dá)隨著疾病的進程而升高，并且Siglec-1的表達(dá)量變化與病毒載量變化呈正相關(guān)，與CD4+T細(xì)胞數(shù)變化呈負(fù)相關(guān)。他們認(rèn)為Siglec-1可以作為一個病毒感染的標(biāo)識分子，也可以看作是免疫系統(tǒng)嚴(yán)重失調(diào)的標(biāo)識物[38]。為了證明Siglec-1在HIV感染過程中的作用，經(jīng)IFN處理的單核巨噬細(xì)胞高表達(dá)Siglec-1， Siglec-1與HIV gp120上的唾液酸結(jié)合介導(dǎo)了病毒與細(xì)胞的吸附，這一過程可促進病毒的進入細(xì)胞也可通過結(jié)合了HIV的單核巨噬細(xì)胞可將病毒呈遞給靶細(xì)胞而促進感染[39，40]，同樣，組織中表達(dá)Siglec-1的巨噬細(xì)胞具有促進感染的作用[41]。

在HIV感染過程中，Siglec-1不僅在單核巨噬細(xì)胞上高表達(dá)，也在DC細(xì)胞上表達(dá)，作為唾液酸受體介導(dǎo)病毒反式感染。成熟的DC細(xì)胞可高表達(dá)Siglec-1，Siglec-1通過與HIV-1病毒包膜上的神經(jīng)節(jié)糖苷結(jié)合，可將HIV-1病毒傳遞給其他鄰近細(xì)胞，從而增強HIV-1的反式感染[42,43]。另外， HIV感染引起的免疫活化也可誘導(dǎo)DC細(xì)胞表達(dá)更多的Siglec-1，從而增強了病毒在血液和組織中的反式感染[38]。不同細(xì)胞表達(dá)Siglec-1與HIV-1病毒結(jié)合位置可能不同，在巨噬細(xì)胞中，Siglec-1與HIV-1的結(jié)合是通過與Env蛋白的V1V2區(qū)中的唾液酸結(jié)合，促進HIV-1對細(xì)胞的感染[40,44];而在DC細(xì)胞中Siglec-1是與病毒膜上唾液酸中的GM3結(jié)合促進HIV的反式感染和傳播，而不依賴于與gp120的結(jié)合[42，46]。

在艾滋病的恒河猴模型中，血液中單核細(xì)胞上的Siglec-1的表達(dá)量也增高。在SIV急性感染期，單核細(xì)胞表達(dá)Siglec-1的表達(dá)量迅速升高，并且當(dāng)CD8+T細(xì)胞損耗時，Siglec-1在單核細(xì)胞上的表達(dá)也同樣升高，在淋巴結(jié)中，活化的CD8+T細(xì)胞可靶向Siglec-1陽性巨噬細(xì)胞，從而降低Siglec-1的表達(dá)。在艾滋病模型中Siglec-1陽性巨噬細(xì)胞與CD8+T細(xì)胞的這種聯(lián)系可能為HIV疫苗和藥物研發(fā)提供新思路[47]。

小結(jié)

Siglec-1 作為巨噬細(xì)胞活化的標(biāo)志，其在炎癥反應(yīng)和免疫調(diào)節(jié)中的作用也越來越受到重視。病原體感染通過可IFN或其他細(xì)胞因子誘導(dǎo)單核細(xì)胞、巨噬細(xì)胞和樹突狀細(xì)胞表達(dá)Siglec-1，一方面Siglec-1促進病原體感染，另一方面Siglec-1還可調(diào)節(jié)固有免疫應(yīng)答和適應(yīng)性免疫應(yīng)答；由于炎癥反應(yīng)可誘導(dǎo)Siglec-1表達(dá)，其表達(dá)與疾病進程相關(guān)，可作為對疾病的評估和療效觀察的指標(biāo)，尤其在HIV-1感染過程中Siglec-1的表達(dá)變化，對Siglec-1的進一步研究可能為AIDS的防治提供新的策略，因此對 Siglec-1 的靶向調(diào)節(jié)治療也有望成為一種新的抗炎治療和抗病毒治療的新方法。

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AdvancesinresearchontheroleofSiglec-1indiseases

LI Ke-lei， LI Xiang， CONG Zhe*， XUE Jing*

(Comparative Medicine Center, Peking Union Medical College (PUMC) & Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences (CAMS); Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health; Key Laboratory of Human Diseases Animal Models, State Administration of Traditional Chinese Medicine, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Beijing 100021, China)

Sialoadhesin (Siglec-1 or CD169) is a sialic acid-binding Ig-like lectin expressed selectively on macrophage subsets. In inflammatory response, Siglec-1 can modulate the secretion of MIP-1 alpha / beta, MCP-1, MIP-2 and other cytokines, and promote the occurrence of inflammatory reaction. During viral infection, Siglec-1 can promote the infection and phagocytosis of virus by mediating the binding of pathogens and macrophages. In the regulation of immunity, Siglec-1 can regulate innate immunity and adaptive immunity, by inhibiting the excessive expression of IFN-α and the activation of DC cells. This review mainly focuses on the new advances of research on Siglec-1 in pathogen infections, inflammation and immunoregulation.

Siglec-1; Inflammation; Immunoregulation; HIV

國家科學(xué)項目自然基金，青年科學(xué)基金項目(81301437)；科技部重大專項(2014ZX10001OO1-001-004，2014ZX10001OO1-002-006)。

李克雷(1986-)，男，博士研究生，主要從事病毒學(xué)和免疫學(xué)研究工作。E-mail： leekelei@163.com

叢喆(1972-)，女，副主任技師，從事實驗動物病毒分子生物學(xué)和模型研究工作。E-mail: congz@cnilas.org。

薛婧(1983-)，女，副研究員，碩士生導(dǎo)師，研究方向：病原生物學(xué)和免疫學(xué)。E-mail: xuejing@cnilas.org。

*共同通訊

R-33

A

1671-7856(2017) 12-0109-06

10.3969.j.issn.1671-7856. 2017.12.019

2017-06-01