王咪咪， 王艷紅

復(fù)旦大學(xué)附屬中山醫(yī)院肝內(nèi)科，上海 200032

巨噬細(xì)胞是機體免疫系統(tǒng)的重要組成部分，其表型和功能具有高度異質(zhì)性[1-2]。組織定居巨噬細(xì)胞長期存在于機體各組織器官，如肝臟中的枯否細(xì)胞、肺組織中的肺泡巨噬細(xì)胞、表皮中的朗格漢斯細(xì)胞、骨組織中的破骨細(xì)胞等，參與機體的免疫監(jiān)視、免疫防御、免疫自穩(wěn)，具有組織特異性。早期研究認(rèn)為，組織定居巨噬細(xì)胞來源于成體骨髓單核細(xì)胞；而最新研究發(fā)現(xiàn)，大部分組織的定居巨噬細(xì)胞是在胚胎時期由胚胎前體細(xì)胞分化而來的，這種胚胎來源巨噬細(xì)胞(EDMs)可以通過自我增殖維持?jǐn)?shù)量和功能穩(wěn)定[3]。這一發(fā)現(xiàn)給巨噬細(xì)胞領(lǐng)域提供了新的研究方向。因此，本文將對肝臟中胚胎來源的組織定居巨噬細(xì)胞的起源和功能進(jìn)行綜述，并由此思考和討論目前巨噬細(xì)胞靶向治療的不足和發(fā)展方向。

1 組織定居巨噬細(xì)胞的起源

組織定居巨噬細(xì)胞一直被認(rèn)為是由成體骨髓單核細(xì)胞分化而來的，即骨髓中的造血干細(xì)胞分化為單核細(xì)胞，后者通過血液循環(huán)按照不同的周期進(jìn)入不同的組織器官，分化為組織定居巨噬細(xì)胞。隨著細(xì)胞發(fā)育制圖技術(shù)[4]等新技術(shù)的研究應(yīng)用，對組織定居巨噬細(xì)胞的起源有了新的認(rèn)識。一般認(rèn)為，在出生之前，胚胎前體細(xì)胞就已分化形成組織定居巨噬細(xì)胞，稱為EDMs。這種細(xì)胞的發(fā)育途徑主要分為3個連續(xù)的造血波[5]，分別命名為原始造血、暫時決定性造血和決定性造血，分別起源于中胚層背側(cè)板胚外卵黃囊中的血島、卵黃囊生血內(nèi)皮細(xì)胞和胚胎內(nèi)生血內(nèi)皮細(xì)胞在主動脈旁臟壁層區(qū)域產(chǎn)生的未成熟的造血干細(xì)胞，分別產(chǎn)生卵黃囊巨噬細(xì)胞、胎肝單核細(xì)胞來源的巨噬細(xì)胞和胎肝單核細(xì)胞。它們都可在機體出生前遷移至器官組織中直接增殖或分化為組織定居巨噬細(xì)胞。

2 EDMs的自我更新與穩(wěn)態(tài)維持

“自我更新”是廣泛應(yīng)用于干細(xì)胞的概念，即在長期不斷的增殖過程中，子細(xì)胞仍能保留母細(xì)胞特性[3]。靜息狀態(tài)下，大部分組織器官(腸、皮膚、心臟、胰腺等)中EDMs無法單獨通過局部自我增殖以維持?jǐn)?shù)量，需要骨髓造血干細(xì)胞的分化補充[5]。因此，大部分組織定居巨噬細(xì)胞群由EDMs和骨髓單核細(xì)胞來源的巨噬細(xì)胞共同構(gòu)成。而肝組織定居巨噬細(xì)胞的來源中，EDMs占絕大多數(shù)，并通過局部自我更新和增殖維持?jǐn)?shù)量，而不依賴于骨髓單核細(xì)胞的補充。有研究[6]報道，肝EDMs的自我更新功能在肝臟微環(huán)境穩(wěn)態(tài)下可以長期保持，不隨年齡增長而逐漸消失。但當(dāng)其離開肝臟微環(huán)境，就會喪失自我更新功能[7]。

當(dāng)機體遇到刺激后，EDMs會發(fā)生不同程度的壞死，嚴(yán)重時候數(shù)量甚至?xí)抵翞?(消失期)[8-9]，再通過局部自我增殖恢復(fù)數(shù)量。由于刺激因素的種類、強度、時間的不同，其恢復(fù)水平和能力會有所變化。研究顯示，非基因毒性刺激(如白喉毒素、氯磷酸二鈉脂質(zhì)體或寄生蟲感染)下，EDMs可局部自我增殖，并在IL-4的作用下極化為M2型，此時不需要骨髓單核細(xì)胞的分化補充[10-11]；而基因毒性(如致死性放射、骨髓移植[11])，李斯特菌、沙門桿菌等胞內(nèi)菌感染，病毒感染等刺激下，壞死的巨噬細(xì)胞可通過分泌CCL2等趨化因子，誘導(dǎo)單核細(xì)胞浸潤肝組織，從而代替EDMs，形成新的組織定居巨噬細(xì)胞[8-9,12-13]，此后，肝臟定居巨噬細(xì)胞池的構(gòu)成比例發(fā)生變化，維持穩(wěn)態(tài)的能力下降。另外，動物實驗[14]表明，如果調(diào)整刺激強度(細(xì)菌載量或放射劑量)，肝臟內(nèi)會出現(xiàn)EDMs與骨髓來源的巨噬細(xì)胞嵌合的狀態(tài)。以上3種情況顯示，一旦穩(wěn)態(tài)被打破，巨噬細(xì)胞池的構(gòu)成將根據(jù)微環(huán)境的不同而發(fā)生變化，進(jìn)而導(dǎo)致不同表現(xiàn)的炎癥反應(yīng)。

3 EDMs介導(dǎo)炎癥反應(yīng)

在肝臟中，EDMs位于肝血竇內(nèi)，黏附于肝血竇內(nèi)皮細(xì)胞上，直接暴露在血液中，是對損傷或刺激產(chǎn)生反應(yīng)的一線細(xì)胞[15]，較骨髓單核系統(tǒng)來源的巨噬細(xì)胞能夠更快速更有效地吞噬衰老細(xì)胞、細(xì)菌、病毒等。EDMs通過其強大的吞噬功能，控制有害物質(zhì)播散[16-18]，減少過度炎癥反應(yīng)對肝臟造成的損傷[16]。

病毒、細(xì)菌和壞死的肝細(xì)胞均能釋放損傷相關(guān)分子模式(DAMPs)、病原體相關(guān)分子模式(PAMPs)，后者通過與清道夫受體(SPs)、toll樣受體(TLRs)、髓細(xì)胞觸發(fā)受體-1(TREM-1)[19]等模式受體結(jié)合激活EDMs，使其極化為M1型巨噬細(xì)胞，并分泌白細(xì)胞介素1(IL-1)、IL-6、腫瘤壞死因子-α(TNF-α)和粒細(xì)胞-巨噬細(xì)胞集落刺激因子(GM-CSF)等促炎因子[20]。此外，一些胞內(nèi)菌(如李斯特菌、沙門桿菌)、X線照射或N-乙酰對氨基苯酚[21]等會導(dǎo)致EDMs大量壞死進(jìn)而激發(fā)單核細(xì)胞、中性粒細(xì)胞的浸潤[8,22]，介導(dǎo)炎癥反應(yīng)的發(fā)生。

隨著炎癥反應(yīng)的進(jìn)展，EDMs會介導(dǎo)抗炎癥反應(yīng)。EDMs可通過分泌TNF，促進(jìn)中性粒細(xì)胞的凋亡，進(jìn)而吞噬凋亡的中性粒細(xì)胞[23]。對凋亡中性粒細(xì)胞的吞噬又可促進(jìn)EDMs產(chǎn)生脂質(zhì)介質(zhì)如脂氧素[24]等，抑制中性粒細(xì)胞的進(jìn)一步浸潤，從而控制過度炎癥反應(yīng)。此外，壞死的EDMs可通過產(chǎn)生IL-1β誘導(dǎo)肝細(xì)胞分泌IL-33，進(jìn)而刺激嗜酸性粒細(xì)胞分泌IL-4；而IL-4能誘導(dǎo)單核來源的巨噬細(xì)胞從M1型轉(zhuǎn)化為M2型[8]，同時可作用于尚存的EDMs，使其局部增殖并分化為M2型巨噬細(xì)胞，后者通過分泌IL-10，活化精氨酸酶，進(jìn)而刺激單核細(xì)胞來源的M1型巨噬細(xì)胞的凋亡[25]。M2型巨噬細(xì)胞能通過分泌大量抗炎因子，如TGF-β、IL-10等，削弱炎癥反應(yīng)，介導(dǎo)免疫耐受[26]。

總之，及時、適度的炎癥有利于清除病原體、凋亡壞死的細(xì)胞以及細(xì)胞碎片等，而過度的炎癥反應(yīng)或者持續(xù)的慢性炎癥則是惡性病變的重要危險因素[27-29]。EDMs在平衡炎癥反應(yīng)和免疫恢復(fù)中發(fā)揮舉足輕重的作用，能夠有效避免病變的發(fā)生。

4 EDMs影響HCC和循環(huán)腫瘤細(xì)胞在肝臟中的生長

炎癥與腫瘤息息相關(guān)，巨噬細(xì)胞是炎癥相關(guān)的重要細(xì)胞[30]。其中，位于腫瘤組織內(nèi)或腫瘤周圍組織的腫瘤相關(guān)性巨噬細(xì)胞(TAMs)[31-34]是一類分化終末期的巨噬細(xì)胞[35]。TAMs顯示與M2型相似的分子功能譜[36-37]，在HCC的發(fā)展和轉(zhuǎn)移過程中起至關(guān)重要的作用[38-40]。有文獻(xiàn)[41-42]認(rèn)為，TAMs是由骨髓單核細(xì)胞分化并在腫瘤微環(huán)境內(nèi)極化為M2型的髓系巨噬細(xì)胞。關(guān)于腫瘤組織中EDMs的功能的相關(guān)報道不多。有實驗[43]顯示，HCC微環(huán)境中，EDMs的抗原遞呈功能下降、CD86和主要組織相容性復(fù)合體Ⅱ分子(MHC-Ⅱ)表達(dá)下降、細(xì)胞程序死亡配體1(PD-L1)表達(dá)上升。腫瘤中髓系來源的抑制細(xì)胞(MDSCs)作用于EDMs，抑制其分泌CCL2和IL-18，而促進(jìn)其分泌IL-10和IL-1β，并使其表面正性和負(fù)性共刺激分子失平衡，從而促進(jìn)HCC的發(fā)展。

雖然EDMs在腫瘤發(fā)展后期呈現(xiàn)促進(jìn)腫瘤生長和轉(zhuǎn)移的作用。但作為一線免疫細(xì)胞又具有抵抗循環(huán)腫瘤細(xì)胞進(jìn)入肝臟的作用[44-48]。其機制主要有：直接吞噬作用[44-50]，降低腫瘤細(xì)胞對肝竇的黏附[45]；通過釋放一氧化氮和活性氧來上調(diào)死亡因子配體(FASL)，誘導(dǎo)腫瘤細(xì)胞的凋亡[51]；通過分泌細(xì)胞因子如IL-1、IL-6、IL-8、TNF-α、γ-干擾素(IFN-γ)，或趨化因子MIP-2、IP-10、KC/GRO、MIP-1α、MCP-1等，激活自然殺傷細(xì)胞(NK)[52]和中性粒細(xì)胞[51]，進(jìn)而殺死循環(huán)腫瘤細(xì)胞。

然而，轉(zhuǎn)移灶或預(yù)轉(zhuǎn)移龕的微環(huán)境可以抑制EDMs吞噬殺傷循環(huán)腫瘤細(xì)胞的功能。研究[53-54]報道，在結(jié)直腸腫瘤肝轉(zhuǎn)移中，當(dāng)骨髓髓系細(xì)胞被募集到轉(zhuǎn)移灶時，此時預(yù)轉(zhuǎn)移龕、腫瘤微環(huán)境已經(jīng)開始建立，大部分單核細(xì)胞不能分化為巨噬細(xì)胞，滯留為MDSCs，后者通過上調(diào)EDMs表面的負(fù)性T細(xì)胞共刺激分子PD-L1[53-54]，抑制其吞噬效能[46]。

5 EDMs靶向治療的挑戰(zhàn)

目前靶向巨噬細(xì)胞的多種抗腫瘤藥物[55-57]已被逐漸研發(fā)，有些已經(jīng)進(jìn)入臨床試驗階段，表現(xiàn)出良好的臨床效果。這些藥物的作用靶點及機制有減少單核細(xì)胞浸潤、抑制單核來源巨噬細(xì)胞的增殖、控制單核細(xì)胞的分化成熟、消融巨噬細(xì)胞、增強巨噬細(xì)胞吞噬功能、調(diào)控巨噬細(xì)胞的極化方向、對促進(jìn)腫瘤發(fā)展的巨噬細(xì)胞進(jìn)行再教育。

上述策略大多針對單核細(xì)胞及其來源的巨噬細(xì)胞，不適用于EDMs。EDMs表面不表達(dá)CXCR3和CCR2[58]，阻斷CCL2-CCR2并不影響EDMs的局部增殖。兩種來源的巨噬細(xì)胞有相互補充的現(xiàn)象。當(dāng)阻斷CCL2/CCR2[59]或CSF1/CSF1R信號通路后，循環(huán)系統(tǒng)無法及時供給足夠的巨噬細(xì)胞，肝臟定居的EDMs可通過自我增殖補充巨噬細(xì)胞池，從而構(gòu)造免疫抑制的腫瘤微環(huán)境，削弱這條機制靶向的抗腫瘤作用。因此，對兩種來源的巨噬細(xì)胞同時進(jìn)行消融、極化和再教育將是巨噬細(xì)胞靶向藥的研究方向。

此外，多種治療性單克隆抗體通過抗體依賴細(xì)胞介導(dǎo)的細(xì)胞毒作用(ADCC)介導(dǎo)巨噬細(xì)胞吞噬，可以有效地殺傷腫瘤細(xì)胞[60-61]。提高巨噬細(xì)胞吞噬功能的抗腫瘤藥物也在動物研究中取得了顯著效果，如抗CD47抗體[62-64]。

然而，這些研究忽略了巨噬細(xì)胞的來源，而不同來源的巨噬細(xì)胞的吞噬功能不同。研究[48]指出，EDMs具有獨特的Dectin-2依賴的吞噬活性。淋巴細(xì)胞脈絡(luò)叢腦膜炎病毒(LCMV)感染的動物模型的研究[65]結(jié)果顯示，EDMs的吞噬水平保持穩(wěn)態(tài)，而單核細(xì)胞的吞噬功能則顯著受損。EDMs能更有效地吞噬乙?；牡兔芏戎鞍?，而對細(xì)菌的吞噬能力則不如單核細(xì)胞來源巨噬細(xì)胞[14]。最新研究[66]發(fā)現(xiàn)，免疫檢查點抑制劑通過拮抗TAMs表面的PD-1，加強其對腫瘤細(xì)胞的吞噬，而這些TAMs經(jīng)實驗證實屬于單核細(xì)胞來源，而非胚胎來源。因而，對不同來源巨噬細(xì)胞吞噬功能的深入探索可為抗體治療和免疫治療提供更廣闊的視野。

6 小 結(jié)

肝臟定居巨噬細(xì)胞占非實質(zhì)細(xì)胞的35%，占全身組織定居巨噬細(xì)胞的80%～90%[23]。因此，巨噬細(xì)胞是肝臟維持穩(wěn)態(tài)、參與炎癥反應(yīng)、調(diào)控生理和病理變化的重要成員。近年來，對于肝臟EDMs的起源、維持穩(wěn)態(tài)以及介導(dǎo)炎癥反應(yīng)等生理或病理功能的研究有了一定的進(jìn)展，但對于其在HCC微環(huán)境中的表型和功能仍有待進(jìn)一步的探索。闡明EDMs在各種不同的生理或病理狀態(tài)下的反應(yīng)和功能，不僅可以為靶向巨噬細(xì)胞治療提供新的思路，也有利于臨床對肝臟相關(guān)疾病病因認(rèn)識的提高和治療方法的改進(jìn)。

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