半乳糖凝集素-3與巨噬細(xì)胞炎性反應(yīng)的關(guān)系

劉仲尼,楊力明

(哈爾濱醫(yī)科大學(xué)基礎(chǔ)醫(yī)學(xué)院病理生理學(xué)教研室,哈爾濱 150081)

半乳糖凝集素-3與巨噬細(xì)胞炎性反應(yīng)的關(guān)系

劉仲尼,楊力明

(哈爾濱醫(yī)科大學(xué)基礎(chǔ)醫(yī)學(xué)院病理生理學(xué)教研室,哈爾濱 150081)

半乳糖凝集素-3(Galectin-3,Gal-3)是一種30 kDa左右且高度保守的β-半乳糖蛋白,在人體各組織及微環(huán)境內(nèi)廣泛存在.由于Gal-3特有的糖識別結(jié)構(gòu)域和高度保守的N-端結(jié)構(gòu)域,使其具有可塑性強(qiáng)和功能多樣化的特點,并在人體內(nèi)作為特殊中介物參與炎癥反應(yīng).巨噬細(xì)胞作為主要的炎性反應(yīng)細(xì)胞對調(diào)節(jié)炎癥反應(yīng)起關(guān)鍵作用.主要介紹Gal-3作為炎性細(xì)胞因子在炎癥中與巨噬細(xì)胞的關(guān)系及研究進(jìn)展.

半乳糖凝集素- 3;巨噬細(xì)胞;炎癥

半乳糖凝集素是一種糖結(jié)合蛋白,以高度保守的N-端氨基酸序列和特異性識別的β-半乳糖苷結(jié)構(gòu)為突出特點[1],受到了國內(nèi)外研究者的廣泛關(guān)注.凝集素共分為三類：動物凝集素、植物凝集素、微生物凝集素,半乳糖凝集素-3(Galectin-3,Gal-3)屬于動物凝集素.已有很多研究證實,Gal-3可作為炎性因子通過細(xì)胞激活、遷移以及調(diào)節(jié)免疫機(jī)制來參與炎癥反應(yīng),而巨噬細(xì)胞是參與多種免疫反應(yīng)的主要炎癥調(diào)節(jié)細(xì)胞.Papaspyridonos等[2]發(fā)現(xiàn)巨噬細(xì)胞大量表達(dá)Gal-3,因此Gal-3和巨噬細(xì)胞間存在密切關(guān)系.

1 Gal-3的生物學(xué)特性

Gal-3是唯一存在于脊椎動物且只包含一個糖識別結(jié)構(gòu)域(carbohydrate recognition domain,CRD)的半乳糖凝集素,最早被命名為Mac-2抗原,首次于經(jīng)過處理的小鼠腹腔巨噬細(xì)胞中被發(fā)現(xiàn).Mac-2由251個氨基酸殘基組成,包含兩個結(jié)構(gòu)域：一個是由約120個氨基酸組成的N-端結(jié)構(gòu)域,含有高度重復(fù)的串聯(lián)序列[3],重復(fù)序列被基質(zhì)金屬蛋白酶(matrix metalloproteinase,MMP)剪切導(dǎo)致CRD對復(fù)合糖等配體的親和力上升,從而使Gal-3易于形成低聚物[4];另一個是由130個氨基酸組成的類球形CRD,它對β-半乳糖苷具有較強(qiáng)的親和力,并通過調(diào)節(jié)糖類結(jié)合位點使Gal-3參與炎性細(xì)胞增殖凋亡及糖配體識別等生理過程.另外,Gal-3還可介導(dǎo)分子間相互作用,交聯(lián)不同細(xì)胞表面糖蛋白,介導(dǎo)細(xì)胞間或細(xì)胞與細(xì)胞外基質(zhì)蛋白間的結(jié)合,從而調(diào)節(jié)細(xì)胞間粘附作用或誘導(dǎo)細(xì)胞遷移.

2 Gal-3的分布

Gal-3缺乏由內(nèi)質(zhì)網(wǎng)囊泡介導(dǎo)的細(xì)胞外分泌信號肽,因此不能通過經(jīng)典途徑分泌到細(xì)胞外,只能通過非經(jīng)典途徑釋放到細(xì)胞外間隙[5-6].絕大部分的Gal-3位于細(xì)胞質(zhì)內(nèi),尤其是作為炎癥因子廣泛存在于炎性細(xì)胞中,少量表達(dá)在細(xì)胞核及線粒體,一小部分Gal-3被分泌到細(xì)胞外.已有研究表明,Gal-3表達(dá)于多種組織細(xì)胞中,包括消化道、子宮內(nèi)膜及呼吸道上皮細(xì)胞、成纖維細(xì)胞和各組織內(nèi)皮細(xì)胞等[7-8].另外,在多種組織的巨噬細(xì)胞及單核細(xì)胞中均能檢測到Gal-3的表達(dá),這表明Gal-3與巨噬細(xì)胞間存在密切關(guān)系[9].

3 炎癥中的巨噬細(xì)胞

巨噬細(xì)胞是炎性反應(yīng)中主要的調(diào)節(jié)細(xì)胞,當(dāng)宿主處于感染早期時,巨噬細(xì)胞的主要作用是清除病原體.然而炎癥是把“雙刃劍”,在清除病原體的同時也會損傷正常組織,因此組織修復(fù)和適時的炎癥抑制在炎癥后期對正常組織有重要的保護(hù)作用.已有研究認(rèn)為巨噬細(xì)胞只發(fā)揮促炎作用,但實際上巨噬細(xì)胞是一種多相性細(xì)胞,不同分化類型的巨噬細(xì)胞可調(diào)節(jié)機(jī)體炎癥狀態(tài)并維持其內(nèi)在平衡.在炎癥的不同階段,組織微環(huán)境的改變及細(xì)胞因子變化會誘導(dǎo)巨噬細(xì)胞分化,從而介導(dǎo)促炎或抑炎反應(yīng)[10].通過干擾素-γ及細(xì)菌脂多糖(lipopolysaccharides, LPS)等Th1細(xì)胞因子活化的經(jīng)典巨噬細(xì)胞為Ⅰ型巨噬細(xì)胞(M1),主要在炎癥早期發(fā)揮促炎作用;通過白介素-4(IL-4)、白介素-13(IL-13)等Th2細(xì)胞因子活化的非經(jīng)典巨噬細(xì)胞為Ⅱ型巨噬細(xì)胞(M2),在炎癥后期抑制炎癥過度反應(yīng)并促進(jìn)組織修復(fù)[11].

4 Gal-3在急性巨噬細(xì)胞相關(guān)炎性反應(yīng)中的作用

4.1 Gal-3調(diào)節(jié)巨噬細(xì)胞的促/抑炎功能

近年來,肺炎鏈球菌型急性肺炎在全球范圍內(nèi)的發(fā)病率逐漸升高,抗生素作為傳統(tǒng)的治療手段,隨著病菌耐藥性的提升，其治療效果逐漸減弱[12].當(dāng)肺部感染肺炎球菌時,肺泡巨噬細(xì)胞作為第一道防線發(fā)揮了重要作用：一方面在炎癥早期胞吞病菌及病菌感染的細(xì)胞;另一方面促進(jìn)中性粒細(xì)胞吞噬肺炎鏈球菌,并使中性粒細(xì)胞產(chǎn)生細(xì)胞毒性產(chǎn)物[13].但是細(xì)胞毒性產(chǎn)物在殺傷病原的同時也會損傷正常組織.在炎癥后期反應(yīng)過度時,巨噬細(xì)胞會吞噬凋亡的中性粒細(xì)胞和細(xì)胞殘骸來抑制炎癥.已有研究表明,Gal-3在炎癥早期和晚期能發(fā)揮相反的作用,在肺炎鏈球菌感染的肺泡中檢測到了大量Gal-3沉積并伴隨有中性粒細(xì)胞外溢.另外與肺炎鏈球菌膜分離物一起培養(yǎng)的肺泡巨噬細(xì)胞中有大量Gal-3的存在[14],這表明Gal-3在巨噬細(xì)胞及中性粒細(xì)胞發(fā)揮免疫功能的過程中起到一定的作用.Farnworth等[15]通過建立感染肺炎鏈球菌的Gal-3基因敲除鼠模型,發(fā)現(xiàn)基因敲除鼠的肺組織損傷比普通小鼠組嚴(yán)重,注射Gal-3后,基因敲除鼠肺組織損傷明顯受到控制,從而也證明了Gal-3對巨噬細(xì)胞相關(guān)炎性反應(yīng)有調(diào)節(jié)作用.體外實驗也證明,經(jīng)巨噬細(xì)胞大量表達(dá)的Gal-3可增強(qiáng)下游中性粒細(xì)胞的胞吞作用從而起到促炎作用.同時發(fā)現(xiàn)Gal-3基因敲除的巨噬細(xì)胞對炎癥后期凋亡中性粒細(xì)胞的胞吞作用弱于正常巨噬細(xì)胞,從而指出Gal-3不僅對巨噬細(xì)胞及中性粒細(xì)胞有促炎作用,還可增強(qiáng)巨噬細(xì)胞的胞吞能力,清理中性粒細(xì)胞以防止過度炎癥反應(yīng).由此可見,Gal-3對巨噬細(xì)胞相關(guān)炎癥反應(yīng)有重要調(diào)控作用.

隨著相關(guān)研究的不斷深入,近年來有學(xué)者提出了Gal-3調(diào)節(jié)巨噬細(xì)胞相關(guān)炎性反應(yīng)的分子機(jī)制.Fermino等[16]指出巨噬細(xì)胞分泌的Gal-3可與LPS相互作用并上調(diào)CD11b和活性氧的表達(dá),從而增強(qiáng)LPS與中性粒細(xì)胞表面之間的親和力并激活中性粒細(xì)胞.另有研究表明, Gal-3可結(jié)合N-乙酰氨基乳糖(一種存在于巨噬細(xì)胞表面糖蛋白的糖類)來促進(jìn)巨噬細(xì)胞吞噬凋亡的中性粒細(xì)胞[17].然而確切的分子機(jī)制還不清楚,需要進(jìn)一步研究.

4.2 Gal-3趨化單核/巨噬細(xì)胞

Gal-3的趨化特性在巨噬細(xì)胞炎性反應(yīng)中起關(guān)鍵作用.Sano等[18]發(fā)現(xiàn)Gal-3在高濃度下可以誘導(dǎo)單核細(xì)胞及巨噬細(xì)胞向Gal-3密集區(qū)遷移,然而在低濃度下卻有相反的效果,并且Gal-3的趨化作用可以被乳糖或作用于N-端結(jié)構(gòu)域的Gal-3抗體抑制,表明Gal-3的N-端結(jié)構(gòu)域和CRD都參與趨化反應(yīng).與此同時,體內(nèi)實驗也得到了相同的結(jié)果.Gal-3趨化作用能促進(jìn)巨噬細(xì)胞炎癥的發(fā)展,當(dāng)機(jī)體受損部位有病原體入侵時,巨噬細(xì)胞表達(dá)的Gal-3會吸引外周血中其他巨噬細(xì)胞到達(dá)受損部位,從而加強(qiáng)炎性反應(yīng).然而,Gal-3趨化作用的促炎特性也可以加劇某些疾病的發(fā)展,比如在動脈粥樣硬化斑塊中集聚的巨噬細(xì)胞會釋放Gal-3,并吸引血液中的單核細(xì)胞和巨噬細(xì)胞到達(dá)斑塊部位從而加劇斑塊的不穩(wěn)定性.因此,Gal-3可作為一個全新靶點,通過調(diào)控其趨化特性治療巨噬細(xì)胞相關(guān)疾病.

4.3 Gal-3調(diào)節(jié)巨噬細(xì)胞凋亡

Gal-3在巨噬細(xì)胞炎性反應(yīng)中對其凋亡具有調(diào)節(jié)作用,而且Gal-3對凋亡的調(diào)節(jié)作用與巨噬細(xì)胞的相對位置有密切關(guān)系.已有研究顯示,位于T細(xì)胞內(nèi)的Gal-3可以明顯抑制T細(xì)胞的凋亡,從而增強(qiáng)T細(xì)胞的免疫功能[19],T細(xì)胞外的Gal-3有明顯的促凋亡作用[20].Hsu等[21]在巨噬細(xì)胞上也發(fā)現(xiàn)了相同的現(xiàn)象,Gal-3?/?小鼠的腹腔原代巨噬細(xì)胞相比于正常巨噬細(xì)胞更易發(fā)生凋亡,無Gal-3表達(dá)到細(xì)胞外的RAW264.7巨噬細(xì)胞被誘導(dǎo)凋亡的效果明顯下降[22],所以Gal-3參與了巨噬細(xì)胞凋亡的調(diào)節(jié)過程.雖然如此,關(guān)于Gal-3調(diào)節(jié)巨噬細(xì)胞凋亡的確切機(jī)制還需要進(jìn)一步研究.

5 Gal-3調(diào)節(jié)巨噬細(xì)胞M2型分化

巨噬細(xì)胞分為M1型和M2型,其中M2型巨噬細(xì)胞參與哮喘、纖維化、組織修復(fù)、動脈粥樣硬化等多領(lǐng)域疾病的發(fā)展過程[23-25].已有研究者通過建立卵白蛋白誘導(dǎo)的哮喘小鼠模型指出,無Gal-3表達(dá)的小鼠能引起較高水平的Th1反應(yīng),而Th2反應(yīng)的水平較低[26],證明了Gal-3參與調(diào)節(jié)M2型巨噬細(xì)胞分化.

CD98是一種異源二聚體式的Ⅱ型跨膜糖蛋白,在巨噬細(xì)胞膜上表達(dá)的CD98可以作為Gal-3的受體[27].Rintoul等[28]和Henderson等[29]的研究表明,CD98與巨噬細(xì)胞膜上的β1整聯(lián)蛋白交聯(lián)在一起,受到4F2抗體刺激時CD98-整聯(lián)蛋白復(fù)合體能夠激活肌醇磷脂3-激酶(PI3K),從而激活其下游的信號通路,誘導(dǎo)M2型巨噬細(xì)胞的分化.同時在Gal-3基因敲除的129sv小鼠骨髓原代巨噬細(xì)胞中,M2型巨噬細(xì)胞明顯減少,而M1型的數(shù)量卻沒有受到影響[30].正常小鼠內(nèi)被激活的M2型巨噬細(xì)胞表達(dá)大量Gal-3且其表達(dá)量明顯高于其他M2型標(biāo)記,反之,M1型巨噬細(xì)胞表達(dá)則降低.Mackinnon等[30]通過干擾RNA影響Gal-3,CD98和抑制PI3K的實驗發(fā)現(xiàn),M2型巨噬細(xì)胞分化均被抑制;針對CRD的特異性,Gal-3糖結(jié)合抑制劑也可以抑制IL-4誘導(dǎo)的M2型分化.上述研究證明,Gal-3通過結(jié)合CD98復(fù)合體在4F2抗體的作用下激活PI3K通路,從而激活M2型巨噬細(xì)胞,而且CRD在這一過程中起到了重要作用(見圖1).另外,細(xì)胞外的Gal-3可以通過限制細(xì)胞膜內(nèi)受體的遷移來延長作用時間,作用后的Gal-3可在IL-4的介導(dǎo)下被巨噬細(xì)胞內(nèi)吞以避免細(xì)胞間隙酶類的降解,被內(nèi)吞的Gal-3釋放后可再次作用于CD98受體[31].

圖1 Gal-3介導(dǎo)的M2型巨噬細(xì)胞分化模式Fig.1 Model of Gal-3 mediated M2 macrophage differentiation

6 Gal-3在慢性巨噬細(xì)胞相關(guān)炎性反應(yīng)中的作用

當(dāng)炎癥長期反復(fù)發(fā)作便會轉(zhuǎn)為慢性并損傷機(jī)體,早期從炎癥轉(zhuǎn)變?yōu)槔w維化,組織正常結(jié)構(gòu)改變,最終導(dǎo)致器官衰竭.在組織纖維化的進(jìn)程中,巨噬細(xì)胞對其發(fā)生發(fā)展起到了重要作用,而巨噬細(xì)胞相關(guān)炎癥因子Gal-3與纖維化的關(guān)系受到了學(xué)者的廣泛關(guān)注.

Henderson等[32]通過建立腎纖維化小鼠模型發(fā)現(xiàn)腎纖維化小鼠體內(nèi)Gal-3高表達(dá),并且Gal-3缺失能夠抑制腎纖維化,同時特異性刪除巨噬細(xì)胞的CD11b-DTR轉(zhuǎn)基因鼠被誘導(dǎo)腎纖維化的程度明顯降低.另外,被移植野生型巨噬細(xì)胞的Gal-3基因敲除鼠恢復(fù)了纖維化.上述實驗證明,巨噬細(xì)胞及其表達(dá)的Gal-3在纖維化的發(fā)展中起重要作用.Henderson等[32]還以Gal-3?/?巨噬細(xì)胞上清液為基質(zhì)培養(yǎng)野生型巨噬細(xì)胞與成纖維細(xì)胞,實驗結(jié)果證明巨噬細(xì)胞分泌的Gal-3能激活成纖維細(xì)胞從而促進(jìn)纖維化的發(fā)展.這些研究表明,Gal-3能夠促進(jìn)有巨噬細(xì)胞參與的慢性纖維化過程.Vergaro等[33]指出Gal-3與醛固酮的協(xié)同作用可促進(jìn)巨噬細(xì)胞浸潤和纖維化的發(fā)展,也有研究表示Gal-3促進(jìn)巨噬細(xì)胞相關(guān)的纖維化過程可能與白介素-33的介導(dǎo)有關(guān)[34],但是具體的分子機(jī)制尚未得到明確解釋.

已有研究顯示,M2型巨噬細(xì)胞的分化對纖維化的發(fā)展有促進(jìn)作用,IL4/IL13誘導(dǎo)的M2型巨噬細(xì)胞提高了纖維化相關(guān)基因的表達(dá)[35-36]并且還能刺激纖維連結(jié)蛋白及其他細(xì)胞外基質(zhì)蛋白的產(chǎn)生[37-38].Liu等[36]也提到經(jīng)處理缺乏IL-4,IL-13或IL-4受體的小鼠肺纖維化明顯減弱.上述研究證明,Gal-3,M2型巨噬細(xì)胞及纖維化三者間存在密切聯(lián)系,但這三者間的相互作用機(jī)制還有待深入研究.

7 展望

Gal-3作為炎癥不同階段功能多樣的炎性因子,在早期促進(jìn)巨噬細(xì)胞相關(guān)炎性反應(yīng),增強(qiáng)免疫;在晚期抑制巨噬細(xì)胞相關(guān)炎性反應(yīng),促進(jìn)組織修復(fù).Gal-3還可趨化巨噬細(xì)胞,調(diào)節(jié)巨噬細(xì)胞凋亡、分化,促進(jìn)巨噬細(xì)胞相關(guān)慢性纖維化.Gal-3對巨噬細(xì)胞相關(guān)炎癥的重要調(diào)節(jié)作用體現(xiàn)出巨大的研究價值,然而Gal-3在巨噬細(xì)胞相關(guān)炎性反應(yīng)中的作用機(jī)制還需深入探討.PI3K作為經(jīng)典自噬通路中重要的一環(huán)可受Gal-3的調(diào)控,這預(yù)示著Gal-3與自噬間可能存在重要聯(lián)系.另外,Gal-3的多樣功能在很大程度上依靠基質(zhì)金屬蛋白酶(matrix metall proteinase,MMP)對其N-端結(jié)構(gòu)域的修飾來實現(xiàn),已有研究指出經(jīng)MMP-7作用后的Gal-3可加劇炎癥反應(yīng)抑制組織修復(fù)[39],因此MMP也可看作是一個探究Gal-3在巨噬細(xì)胞相關(guān)炎性反應(yīng)中作用的新視角.同時,對Gal-3與巨噬細(xì)胞相關(guān)炎性反應(yīng)的深入研究不僅在基礎(chǔ)領(lǐng)域有重要意義,在臨床領(lǐng)域譬如動脈粥樣硬化等巨噬細(xì)胞相關(guān)疾病的治療方面也具有指導(dǎo)意義.

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Relationship between galectin-3 and macrophage in inflammation reactions

LIU Zhongni,YANG Liming
(Department of Pathophysiology,School of Basic Medical Sciences,Harbin Medical University, Harbin 150081,China)

Galectin-3(Gal-3)is an approximately 30 kDa and highly conserved β-galactose distributed in a wide range of tissues and microenvironments.Its specific carbohydraterecognition domain and evolutionary conserved N-terminal domain of Gal-3 make it more flexible and multifunctional as a mediator affecting inflammation.Macrophage plays an important role in inflammatory reactions as a major immunocyte.This review focuses on the relationship between Gal-3 and macrophage in inflammatory reactions.

Galectin-3(Gal-3);macrophage;inflammation

R 392.12

A

1007-2861(2017)03-0395-07

10.12066/j.issn.1007-2861.1886

2016-12-20

國家自然科學(xué)基金資助項目(81571833,81271734,81000688);黑龍江省自然科學(xué)基金資助項目(H2015006)

楊力明(1978—),男,教授,博士,研究方向為聲光敏劑介導(dǎo)的聲光動力治療動脈粥樣硬化. E-mail：cooperationyang@126.com