巨噬細(xì)胞在血管炎癥及動脈粥樣硬化中的作用

孫雨萌，左海奇，田野

動脈粥樣硬化（AS）以血管壁的慢性炎癥反應(yīng)為特征，其并發(fā)癥心肌梗死和腦卒中等是全球首要致死疾病。巨噬細(xì)胞是AS病變中最豐富的一類細(xì)胞，從AS病變形成到斑塊破裂的各個階段都起著重要作用。當(dāng)局部區(qū)域的血流處于非層流狀態(tài)時，血管內(nèi)皮功能障礙導(dǎo)致循環(huán)低密度脂蛋白（LDL）滲透到血管內(nèi)膜，高脂血癥患者尤為明顯，血管壁上LDL經(jīng)過氧化等修飾后激活內(nèi)皮細(xì)胞和固有免疫細(xì)胞，導(dǎo)致趨化因子和粘附分子表達(dá)增加，趨化循環(huán)中單核細(xì)胞在血管壁的粘附、滾動、跨內(nèi)皮遷移，導(dǎo)致內(nèi)膜單核細(xì)胞浸潤。單核細(xì)胞進(jìn)入血管內(nèi)膜后，分化成巨噬細(xì)胞攝取修飾后的脂蛋白成為泡沫細(xì)胞。逐漸積累在內(nèi)皮的泡沫細(xì)胞凋亡，若凋亡的泡沫細(xì)胞沒有被及時清除，逐漸導(dǎo)致血栓和炎性壞死核心的形成。巨噬細(xì)胞通過分泌細(xì)胞因子和蛋白水解酶進(jìn)一步加劇炎癥，導(dǎo)致斑塊穩(wěn)定性下降、破裂繼發(fā)血栓形成，引起缺血性事件如心肌梗死、中風(fēng)。這一觀點被認(rèn)為是損傷形成的重要機(jī)制。但最近有研究揭示了AS斑塊中巨噬細(xì)胞聚集的機(jī)制及功能。

1 巨噬細(xì)胞在血管壁聚集的機(jī)制

1.1 骨髓和脾臟來源的循環(huán)單核細(xì)胞募集 在AS病變進(jìn)展中，循環(huán)中的單核細(xì)胞向炎癥血管募集。在高膽固醇小鼠模型中，給予高脂飲食，Ly-6Chi單核細(xì)胞集群明顯增多，Ly-6Chi單核細(xì)胞粘附于活化的血管內(nèi)皮細(xì)胞、病灶轉(zhuǎn)變成巨噬細(xì)胞。Ly-6Chi CCR2+型單核細(xì)胞為斑塊內(nèi)巨噬細(xì)胞的主要前體細(xì)胞，其向斑塊募集主要取決于趨化因子受體CCR2、CCR5和CX3CR1的表達(dá)[1,2]以及內(nèi)皮細(xì)胞上各種粘附分子受體的表達(dá)[3]。骨髓產(chǎn)生的單核細(xì)胞一直被認(rèn)為是AS主要病變中單核細(xì)胞來源，并且高脂血癥以及高血糖能夠促進(jìn)骨髓產(chǎn)生單核細(xì)胞[4,5]。有研究證實[6]，趨化因子受體CCR2介導(dǎo)了骨髓來源的Ly-6Chi單核細(xì)胞游走。有研究提示造血干細(xì)胞（HSC）從骨髓遷移到脾臟進(jìn)一步分化為成熟單核細(xì)胞，在粥樣硬化病變部位大量聚集[7]。與CCR2介導(dǎo)的機(jī)制不同，脾源性單核細(xì)胞募集依賴于血管緊張素Ⅱ 1型受體AT1[8]，脾臟單核細(xì)胞受到血管緊張素II刺激后開始動員[9]。

1.2 巨噬細(xì)胞局部增殖 目前AS斑塊中巨噬細(xì)胞聚集的機(jī)制尚不明確。Robbins等[10]發(fā)現(xiàn)在病變部位固有巨噬細(xì)胞增殖約占87%，而循環(huán)招募巨噬細(xì)胞僅在疾病早期出現(xiàn)。AS病變形成過程中，隨著病變部位增大單核細(xì)胞募集不斷增多，同時，高血脂時單核細(xì)胞募集加強(qiáng)[11]。Sárka L等學(xué)者指出在病變早期巨噬細(xì)胞增殖活性較高，晚期則反之[12]。而且近來發(fā)現(xiàn)病變部位中一部分巨噬細(xì)胞是不能增殖的衰老細(xì)胞，可用藥物清除[13]。在損傷后以及AS斑塊中，小部分可塑血管平滑肌細(xì)胞（VSMC）廣泛增殖可導(dǎo)致其積聚[14-16]。

1.3 VSMC分化為巨噬細(xì)胞樣細(xì)胞 之前研究發(fā)現(xiàn)AS病變中巨噬細(xì)胞和VSMC共表達(dá)細(xì)胞標(biāo)記物[17]，最近研究表明[18]，病變部位高達(dá)50%細(xì)胞為表達(dá)平滑肌細(xì)胞標(biāo)志物的巨噬細(xì)胞。但該研究并不能確定這些細(xì)胞是源于VSMC標(biāo)記物上調(diào)還是VSMCs轉(zhuǎn)化為巨噬細(xì)胞。Feil等[15]研究表明在AS晚期，通過他莫昔芬誘導(dǎo)的Cre重組酶的表達(dá)，VSMC失標(biāo)記并轉(zhuǎn)化為克隆擴(kuò)增的VSMC源性的類巨噬細(xì)胞。但Shankman等[16]指出，VSMC在AS斑塊中發(fā)揮重要作用，同時敲除KLF4的VSMC表型在病變中也發(fā)揮重要作用。體外實驗證實[19]，高膽固醇可誘導(dǎo)VSMC轉(zhuǎn)變?yōu)榫奘杉?xì)胞樣細(xì)胞。這些VSMC源性的巨噬細(xì)胞樣細(xì)胞有著與骨髓源性巨噬細(xì)胞不同的轉(zhuǎn)錄譜，且無經(jīng)典巨噬細(xì)胞功能[20]。

1.4 大動脈固有巨噬細(xì)胞和局部分化巨噬細(xì)胞 正常動脈壁存在固有巨噬細(xì)胞和樹突狀細(xì)胞。研究表明小鼠動脈壁含有兩種不同來源的固有巨噬細(xì)胞，即CX3CR1+胚胎前體和出生后骨髓來源的單核細(xì)胞，這類血管中的巨噬細(xì)胞通過自我更新補充感染時的消耗來維持穩(wěn)態(tài)[21]。除了動脈壁固有巨噬細(xì)胞，一些研究提出在小鼠主動脈外膜上存在一定數(shù)量的巨噬細(xì)胞祖細(xì)胞，可局部分化促進(jìn)AS中巨噬細(xì)胞的聚集[22]。

胚胎發(fā)育過程中，來源于干細(xì)胞的組織固有巨噬細(xì)胞概念的提出對傳統(tǒng)單核細(xì)胞轉(zhuǎn)化為巨噬細(xì)胞的模式提出挑戰(zhàn)[23]。特定組織的巨噬細(xì)胞來源于各種不同前體細(xì)胞，如卵黃囊源性祖細(xì)胞胚胎造血干細(xì)胞或成人造血干細(xì)胞來源的單核細(xì)胞[23]。分析巨噬細(xì)胞來源、動脈固有巨噬細(xì)胞和巨噬細(xì)胞前體細(xì)胞對AS防治意義重大。

1.5 巨噬細(xì)胞與斑塊消退 逆轉(zhuǎn)小鼠高膽固醇血癥，斑塊中的巨噬細(xì)胞減少同時斑塊也減小[24]。將AS或肝臟X受體（LXR）缺失的小鼠動脈移植到野生型小鼠體內(nèi)，斑塊消退，趨化因子受體CCR7表達(dá)[25]。此外，van等進(jìn)一步提出，損傷部位的巨噬細(xì)胞能夠表達(dá)軸突導(dǎo)向因子及其受體等，抑制巨噬細(xì)胞遷移出病變部位，促進(jìn)斑塊進(jìn)展[26]。另有研究提出[24]，受損部位巨噬細(xì)胞的消退主要由CCR7介導(dǎo)。

2 巨噬細(xì)胞在動脈粥樣硬化中的作用

2.1 炎癥細(xì)胞因子和蛋白酶的產(chǎn)生 在損傷部位，巨噬細(xì)胞通過產(chǎn)生促炎因子及趨化因子來募集免疫細(xì)胞，參與炎癥反應(yīng)。斑塊中巨噬細(xì)胞表達(dá)促炎因子能夠加速AS進(jìn)展，如腫瘤壞死因子-α（TNF-α）[27]和白介素-18（IL-18）[28]等。在Apoe-/-小鼠中，骨髓細(xì)胞白介素-1α（IL- 1α）和白介素-1β（IL-1β）表達(dá)缺失，導(dǎo)致AS損傷及炎癥減輕[29]。骨髓細(xì)胞過表達(dá)趨化因子CCL2增加巨噬細(xì)胞在病變聚集，提示白細(xì)胞趨化因子促進(jìn)斑塊炎癥進(jìn)展[30]。此外，AS斑塊中的巨噬細(xì)胞也能產(chǎn)生抗炎因子，白介素-13（IL-13）表達(dá)下降可加重斑塊炎癥及損傷[31]。

AS病變處蛋白水解程度與斑塊易損和破裂相關(guān)，損傷處巨噬細(xì)胞蛋白水解活性較高，導(dǎo)致斑塊易損和破裂[32]。Apoe-/-小鼠中證實病變晚期的巨噬細(xì)胞過表達(dá)基質(zhì)金屬蛋白酶-9（MMP-9），進(jìn)而導(dǎo)致斑塊易損性增加[32]。而Ldlr-/-小鼠骨髓源性巨噬細(xì)胞未表達(dá)基質(zhì)金屬蛋白酶-14（MMP-14），導(dǎo)致膠原含量增加、斑塊穩(wěn)定，這提示巨噬細(xì)胞表達(dá)的MMP-14與易損斑塊形成相關(guān)[33]。

2.2 泡沫細(xì)胞的形成 巨噬細(xì)胞源性泡沫細(xì)胞在血管內(nèi)皮形成。巨噬細(xì)胞胞內(nèi)脂質(zhì)積聚程度反映了胞外脂質(zhì)攝取和逆向脂質(zhì)運輸之間的平衡。巨噬細(xì)胞通過各種清道夫受體吞噬修飾后的低密度脂蛋白（LDL），例如清道夫受體A1（MSR1）、LDL受體相關(guān)蛋白1（LRP-1）以及凝集素樣氧化低密度脂蛋白受體1（LOX-1）[34]。高脂飼料喂養(yǎng)的Ldlr-/-小鼠LRP-1缺乏導(dǎo)致膽固醇在巨噬細(xì)胞聚集減少，但血液中血脂的積累并未減少，表明LRP-1減少AS損傷部位泡沫細(xì)胞形成[35]。抑制泡沫細(xì)胞形成與CD36及MSR1缺乏相關(guān)。研究指出抑制Apoe-/-小鼠CD36或MSR1表達(dá)時，盡管膽固醇在巨噬細(xì)胞的積聚減少，但仍有泡沫細(xì)胞聚集，提示脂質(zhì)攝取替代途徑可以彌補CD36或MSR1的缺失[36]。除了對脂質(zhì)攝取的調(diào)節(jié)作用，MSR1在AS病變晚期對巨噬細(xì)胞聚集也起重要作用[10]。表達(dá)于AS斑塊巨噬細(xì)胞的黏附分子受體CD146，通過增加CD36內(nèi)化進(jìn)一步促進(jìn)氧化低密度脂蛋白的積聚。此外，CD146也能促進(jìn)巨噬細(xì)胞在病變部位固定[37]。

巨噬細(xì)胞膽固醇流出依賴于ATP結(jié)合盒轉(zhuǎn)運蛋白（ABC）ABCA1和ABCG1[38]。ABCA1和ABCG1相關(guān)的膽固醇流出途徑不僅能調(diào)節(jié)泡沫細(xì)胞形成，還能夠抑制造血干/祖細(xì)胞（HSPC）增殖和動員[39,40]，Acba1-/-Abcg1-/-小鼠造血干/組細(xì)胞過度增殖，白細(xì)胞增多，髓外造血增加，引起免疫細(xì)胞在病變部位聚集。

3 巨噬細(xì)胞增殖、衰老、存活、凋亡

在AS病變晚期巨噬細(xì)胞增殖被激活。與增殖型巨噬細(xì)胞相比，病變部位也存在失去增殖能力的細(xì)胞即衰老細(xì)胞。研究指出內(nèi)膜上的巨噬細(xì)胞源性衰老泡沫細(xì)胞參與AS的整個過程[17]。高脂飼料喂養(yǎng)的Ldlr-/-小鼠中，主動脈弓部血管內(nèi)膜巨噬細(xì)胞源性泡沫細(xì)胞衰老標(biāo)志物高表達(dá)，藥物清除這些細(xì)胞后，TNF-α、血管粘附分子-1（VCAM-1）和單核細(xì)胞趨化蛋白-1（MCP-1）表達(dá)下降。在AS病變部位，有研究發(fā)現(xiàn)約20%的巨噬細(xì)胞源性泡沫細(xì)胞表達(dá)衰老標(biāo)記物，衰老的巨噬細(xì)胞增加了炎性細(xì)胞因子和基質(zhì)金屬蛋白酶的表達(dá)，清除衰老細(xì)胞能抑制疾病進(jìn)展、促進(jìn)斑塊穩(wěn)定[13]。巨噬細(xì)胞在血脂水平正常后消退斑塊和炎癥[24]。

3.1 胞葬和自噬 胞葬是免疫沉默時通過巨噬細(xì)胞吞噬來清除凋亡細(xì)胞并且是維持自身免疫耐受的過程[41]，有研究表明巨噬細(xì)胞的胞葬能力與AS的發(fā)生發(fā)展相關(guān)[42]。研究證實[43]，MFGE8橋接凋亡細(xì)胞膜表達(dá)的磷脂酰絲氨酸（PS）和巨噬細(xì)胞上的αvβ3/β5整合素，并且免疫細(xì)胞特異性缺失MFG-E8AS的Ldlr-/-小鼠AS病變和壞死增加。最近有研究提出巨噬細(xì)胞表面MER-Tk裂解能夠在AS病變中減少胞葬作用，而Ldlr-/-小鼠抗MER-TK裂解可促進(jìn)胞葬作用、減少壞死[44]。在巨噬細(xì)胞表達(dá)的T細(xì)胞免疫球蛋白黏蛋白域蛋白-1（TIM-1）或TIM-4可以識別凋亡細(xì)胞上PS，Ldlr-/-小鼠中TIM-1或TIM-4表達(dá)受到抑制[45]，或補體C1q基因缺乏，均減少凋亡細(xì)胞的清除，導(dǎo)致AS損傷加重[46]。凋亡細(xì)胞還能夠表達(dá)“別吃我”信號，如CD47，其能夠通過與巨噬細(xì)胞表面受體SIRPα結(jié)合阻止胞葬作用，且近來發(fā)現(xiàn)在AS小鼠模型中通過單克隆抗體競爭中和CD47能減少損傷形成、促進(jìn)胞葬作用[47]。提示，胞葬可作為AS重要的治療靶點。并且，巨噬細(xì)胞吞噬凋亡細(xì)胞促進(jìn)了抗炎作用，其高表達(dá)抗炎因子白介素-10（IL-10）、轉(zhuǎn)錄生長因子-β（TGF-β）并減少促炎因子白介素-12（IL-12）和轉(zhuǎn)錄生長因子-α（TNF-α）的表達(dá)[48]。此外，凋亡細(xì)胞被吞噬觸發(fā)其表達(dá)LXR依賴的MER-TK進(jìn)一步促進(jìn)胞葬作用[49]。

自噬可誘導(dǎo)斑塊巨噬細(xì)胞氧化應(yīng)激和內(nèi)質(zhì)網(wǎng)應(yīng)激，若自噬相關(guān)-5基因（Atg-5）缺乏，斑塊巨噬細(xì)胞凋亡和壞死則增加。并且，Atg-5缺乏時凋亡細(xì)胞不能有效通過巨噬細(xì)胞胞葬作用被清除[50]。這些結(jié)果提示巨噬細(xì)胞自噬在晚期AS中起保護(hù)作用。綜上所述，了解巨噬細(xì)胞在血管炎癥和動脈粥樣硬化中的功能和具體機(jī)制，為疾病的治療提供新思路。需不斷深入研究巨噬細(xì)胞以及其在AS中的具體作用。

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