胚胎來源巨噬細胞的起源及其在肝臟中功能的研究進展

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]。組織定居巨噬細胞長期存在于機體各組織器官，如肝臟中的枯否細胞、肺組織中的肺泡巨噬細胞、表皮中的朗格漢斯細胞、骨組織中的破骨細胞等，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。早期研究認為，組織定居巨噬細胞來源于成體骨髓單核細胞；而最新研究發(fā)現(xiàn)，大部分組織的定居巨噬細胞是在胚胎時期由胚胎前體細胞分化而來的，這種胚胎來源巨噬細胞(EDMs)可以通過自我增殖維持數(shù)量和功能穩(wěn)定[3]。這一發(fā)現(xiàn)給巨噬細胞領(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胞的起源和功能進行綜述，并由此思考和討論目前巨噬細胞靶向治療的不足和發(fā)展方向。

1 組織定居巨噬細胞的起源

組織定居巨噬細胞一直被認為是由成體骨髓單核細胞分化而來的，即骨髓中的造血干細胞分化為單核細胞，后者通過血液循環(huán)按照不同的周期進入不同的組織器官，分化為組織定居巨噬細胞。隨著細胞發(fā)育制圖技術(shù)[4]等新技術(shù)的研究應(yīng)用，對組織定居巨噬細胞的起源有了新的認識。一般認為，在出生之前，胚胎前體細胞就已分化形成組織定居巨噬細胞，稱為EDMs。這種細胞的發(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)皮細胞和胚胎內(nèi)生血內(nèi)皮細胞在主動脈旁臟壁層區(qū)域產(chǎn)生的未成熟的造血干細胞，分別產(chǎn)生卵黃囊巨噬細胞、胎肝單核細胞來源的巨噬細胞和胎肝單核細胞。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)用于干細胞的概念，即在長期不斷的增殖過程中，子細胞仍能保留母細胞特性[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數(shù)量，需要骨髓造血干細胞的分化補充[5]。因此，大部分組織定居巨噬細胞群由EDMs和骨髓單核細胞來源的巨噬細胞共同構(gòu)成。而肝組織定居巨噬細胞的來源中，EDMs占絕大多數(shù)，并通過局部自我更新和增殖維持數(shù)量，而不依賴于骨髓單核細胞的補充。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。但當其離開肝臟微環(huán)境，就會喪失自我更新功能[7]。

當機體遇到刺激后，EDMs會發(fā)生不同程度的壞死，嚴重時候數(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，壞死的巨噬細胞可通過分泌CCL2等趨化因子，誘導(dǎo)單核細胞浸潤肝組織，從而代替EDMs，形成新的組織定居巨噬細胞[8-9,12-13]，此后，肝臟定居巨噬細胞池的構(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，巨噬細胞池的構(gòu)成將根據(jù)微環(huán)境的不同而發(fā)生變化，進而導(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)的一線細胞[15]，較骨髓單核系統(tǒng)來源的巨噬細胞能夠更快速更有效地吞噬衰老細胞、細菌、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、細菌和壞死的肝細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型巨噬細胞，并分泌白細胞介素1(IL-1)、IL-6、腫瘤壞死因子-α(TNF-α)和粒細胞-巨噬細胞集落刺激因子(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大量壞死進而激發(fā)單核細胞、中性粒細胞的浸潤[8,22]，介導(dǎo)炎癥反應(yīng)的發(fā)生。

隨著炎癥反應(yīng)的進展，EDMs會介導(dǎo)抗炎癥反應(yīng)。EDMs可通過分泌TNF，促進中性粒細胞的凋亡，進而吞噬凋亡的中性粒細胞[23]。對凋亡中性粒細胞的吞噬又可促進EDMs產(chǎn)生脂質(zhì)介質(zhì)如脂氧素[24]等，抑制中性粒細胞的進一步浸潤，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)肝細胞分泌IL-33，進而刺激嗜酸性粒細胞分泌IL-4；而IL-4能誘導(dǎo)單核來源的巨噬細胞從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型巨噬細胞，后者通過分泌IL-10，活化精氨酸酶，進而刺激單核細胞來源的M1型巨噬細胞的凋亡[25]。M2型巨噬細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、凋亡壞死的細胞以及細胞碎片等，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)腫瘤細胞在肝臟中的生長

炎癥與腫瘤息息相關(guān)，巨噬細胞是炎癥相關(guān)的重要細胞[30]。其中，位于腫瘤組織內(nèi)或腫瘤周圍組織的腫瘤相關(guān)性巨噬細胞(TAMs)[31-34]是一類分化終末期的巨噬細胞[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[41-42]認為，TAMs是由骨髓單核細胞分化并在腫瘤微環(huán)境內(nèi)極化為M2型的髓系巨噬細胞。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)表達下降、細胞程序死亡配體1(PD-L1)表達上升。腫瘤中髓系來源的抑制細胞(MDSCs)作用于EDMs，抑制其分泌CCL2和IL-18，而促進其分泌IL-10和IL-1β，并使其表面正性和負性共刺激分子失平衡，從而促進HCC的發(fā)展。

雖然EDMs在腫瘤發(fā)展后期呈現(xiàn)促進腫瘤生長和轉(zhuǎn)移的作用。但作為一線免疫細胞又具有抵抗循環(huán)腫瘤細胞進入肝臟的作用[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)腫瘤細胞的凋亡[51]；通過分泌細胞因子如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，激活自然殺傷細胞(NK)[52]和中性粒細胞[51]，進而殺死循環(huán)腫瘤細胞。

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)腫瘤細胞的功能。研究[53-54]報道，在結(jié)直腸腫瘤肝轉(zhuǎn)移中，當骨髓髓系細胞被募集到轉(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，大部分單核細胞不能分化為巨噬細胞，滯留為MDSCs，后者通過上調(diào)EDMs表面的負性T細胞共刺激分子PD-L1[53-54]，抑制其吞噬效能[46]。

5 EDMs靶向治療的挑戰(zhàn)

目前靶向巨噬細胞的多種抗腫瘤藥物[55-57]已被逐漸研發(fā)，有些已經(jīng)進入臨床試驗階段，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胞浸潤、抑制單核來源巨噬細胞的增殖、控制單核細胞的分化成熟、消融巨噬細胞、增強巨噬細胞吞噬功能、調(diào)控巨噬細胞的極化方向、對促進腫瘤發(fā)展的巨噬細胞進行再教育。

上述策略大多針對單核細胞及其來源的巨噬細胞，不適用于EDMs。EDMs表面不表達CXCR3和CCR2[58]，阻斷CCL2-CCR2并不影響EDMs的局部增殖。兩種來源的巨噬細胞有相互補充的現(xiàn)象。當阻斷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胞，肝臟定居的EDMs可通過自我增殖補充巨噬細胞池，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胞同時進行消融、極化和再教育將是巨噬細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胞介導(dǎo)的細胞毒作用(ADCC)介導(dǎo)巨噬細胞吞噬，可以有效地殺傷腫瘤細胞[60-61]。提高巨噬細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胞的來源，而不同來源的巨噬細胞的吞噬功能不同。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)，而單核細胞的吞噬功能則顯著受損。EDMs能更有效地吞噬乙酰化的低密度脂蛋白，而對細菌的吞噬能力則不如單核細胞來源巨噬細胞[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，加強其對腫瘤細胞的吞噬，而這些TAMs經(jīng)實驗證實屬于單核細胞來源，而非胚胎來源。因而，對不同來源巨噬細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)

肝臟定居巨噬細胞占非實質(zhì)細胞的35%，占全身組織定居巨噬細胞的80%～90%[23]。因此，巨噬細胞是肝臟維持穩(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展，但對于其在HCC微環(huán)境中的表型和功能仍有待進一步的探索。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)疾病病因認識的提高和治療方法的改進。

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