小膠質細胞在神經發育和神經退行性疾病中的吞噬作用與調節機制

李晶文，張 麗，張連峰,2*

(1.中國醫學科學院醫學實驗動物研究所，北京協和醫學院比較醫學中心，衛計委人類疾病比較醫學重點實驗室，北京 100021； 2.中國醫學科學院神經科學中心，北京 100730)

小膠質細胞(microglia)是神經膠質細胞的一種，約占大腦中神經膠質細胞的10%～15%，相當于定居在腦和脊髓中的巨噬細胞。近年來的研究發現，與其他組織巨噬細胞的起源不同，小膠質細胞起源于卵黃囊，并在胚胎發育早期進入腦組織，特化為小膠質細胞[1-2]。這提示小膠質細胞具有其特定的功能。目前已知的小膠質細胞功能包括清除功能、吞噬功能、抗原提呈功能、突觸剝離作用、促進損傷修復和分泌細胞外信號等，在神經發育、腦組織維持、突觸重塑、神經炎癥、腦部感染、細胞毒性以及神經退行性病變等生理和病理過程中發揮著重要作用。

小膠質細胞的吞噬作用(phagocytosis)指受體介導的吞噬和清理腦組織中的“廢物”，維持腦組織穩態的過程。病理狀態下小膠質細胞被激活，活化的小膠質細胞可以吞噬凋亡細胞碎片、癡呆癥患者腦組織中的淀粉樣β蛋白(amyloid-β protein, Aβ)、髓鞘碎片、腦組織內感染病原等多種物質，從而起到清理有害物質、抗炎等作用。在生理狀態下，未經活化的小膠質細胞同樣可以清理大腦發育過程中產生的凋亡細胞以及一些多余的突觸等[3-4]，在腦組織發育、形態發生、突觸重塑等過程中發揮著重要作用。

1 小膠質細胞的吞噬是多步驟的生理病理過程

小膠質細胞的吞噬作用不僅是腦組織內凋亡細胞碎片、髓鞘碎片、感染病原以及癡呆癥患者腦內Aβ淀粉樣蛋白等無用或有害物質清除的主要機制，也是記憶形成時的突觸剝離(synaptic stripping)過程的重要步驟[4-7]。小膠質細胞的吞噬過程十分復雜，涉及到多種分子的參與，至今尚未完全研究清楚。目前被大家廣泛接受的小膠質細胞吞噬模型是類似于巨噬細胞吞噬的三步模型，即吞噬靶標的發現(find me)、吞噬(eat me)和消化(digest me)[8]。

1.1 吞噬靶標的發現

腦組織內的凋亡細胞會釋放ATP和UTP到細胞外，而在細胞外基質中，ATP和UTP會被外核苷酸酶降解為ADP和UDP[9]。膠質細胞的表面存在有多種嘌呤能受體，其中，ATP及其代謝產物可以激活受體P2Y1-14、P2X1-7、P2Y12等P2家族成員，UDP及其代謝產物可以激活 P2Y6；激活的受體可以進一步活化細胞內一系列信號途徑，如PI3K/AKT，進而促使膠質細胞向吞噬靶標運動，或伸出偽足將吞噬靶標包圍[7, 10-13]。

此外，趨化因子、細胞因子、生長因子等也具有增強小膠質細胞清除細胞碎片的作用，如分形趨化因子(CX3CL1)、白介素34(IL-34)、纖維母細胞生長因子(FGF2)等[14-15]。

1.2 吞噬

吞噬過程即受體介導的識別與吞噬過程，小膠質細胞表面的很多受體都參與了這一過程，其中一部分受體介導小膠質細胞與靶標的識別和橋接，另一部分受體激發內在化過程[16]。

根據功能的不同，可將小膠質細胞表面受體簡單地分為兩類。第一類是病原偵測相關分子(detection of pathogen-associated molecular patterns，PAMPS)，主要由清除劑受體(scavenger receptor)與Toll樣受體、免疫球蛋白超家族成員協同作用，對腦部的細菌、真菌等病原進行偵測、橋接吞噬。這類受體包括CD36、CD68、COX-1、MARCO、SR-1、SR-2、TLR2、TLR4、DECTIN-1、MR等[4, 17-21]。第二類是凋亡細胞偵測相關分子(detection of apoptotic cell-associated molecular patterns，ACAMPs)，細胞凋亡時，細胞膜內側的磷脂酰絲氨酸(phosphatidylserine，PS)暴露于細胞膜表面，可以與ACAMPs中最主要的一類受體(PS受體)結合。這類PS受體主要介導小膠質細胞與凋亡細胞的識別，包括BAI-1、MER、PSR、STABILIN-2、TIM-1、TIM-4等[4, 22]；另一類分子可以介導小膠質細胞與凋亡細胞橋接，如乳脂球表皮生長因子(milk fat globule-epidermal growth factor，MFG-E8)等[23]。

此外，還有一些分子可以激發內在化過程，包括整合素家族成員和IgG超家族成員，參與小膠質細胞與靶標的橋接和內在化的激發[24-25]。其中，IgG超家族成員中的TREM2，可以激活SRC/SYK/RAC1等細胞運動相關信號通路，激發內在化過程；同時可以通過抑制RAS/ERK減少炎癥因子分泌[26]。

1.3 消化

腦組織內的凋亡細胞碎片、感染病原、髓鞘碎片、Aβ淀粉樣蛋白等在受體的介導下，形成吞噬體，進一步與早期或晚期胞內體融合，形成吞噬溶酶體。吞噬溶酶體內存在多種水解酶和組織蛋白酶，可以對吞噬的物質進行降解[27]。

2 小膠質細胞的吞噬作用與神經發育

哺乳動物的中樞神經來源于外胚層。人類胚胎發育的第三周左右，在胚胎背側，神經外胚層發育形成神經板，是神經元和膠質細胞的來源。神經板隨后卷曲發育成為神經管。神經管最初由一層增生能力極強的神經上皮構成，不同的部分可分別發育為大腦、小腦、延腦和脊髓等，共同組成構筑精巧、功能精細復雜的神經系統[28]。

神經細胞和膠質細胞的增生、遷移與凋亡，是神經發育和形態發生的關鍵。細胞生長與凋亡之間的平衡失調將會導致各種神經發育畸形和疾病。凋亡神經細胞的清除對于神經的正常發育至關重要，而小膠質細胞吞噬正是神經組織內凋亡細胞清除的主要途徑。小膠質細胞在變形狀態下可以在腦組織中遷移，并在凋亡細胞周圍聚集[29]。有體外培養實驗證實，活化的小膠質細胞可以吞噬死亡的浦肯野細胞和海馬神經元[30-31]。

小膠質細胞的吞噬作用在突觸重塑和環路形成中同樣發揮著關鍵作用[32]。神經發育過程中，不僅有大量的神經元凋亡，同時也伴隨著突觸的重塑過程。哺乳動物出生后，在丘腦、小腦、嗅球、海馬等突觸重塑活躍的腦區都有反應性小膠質細胞的存在，并與未成熟突觸緊密接觸；研究發現小膠質細胞中含有被吞噬的突觸蛋白，證實小膠質細胞可以通過吞噬作用對突觸進行修剪[33-34]。而在成體腦組織中，小膠質細胞也可以通過對突觸的修剪作用影響突觸可塑性。神經元通過突觸網絡通信是認知活動的基礎；而隨著年齡增加，神經元樹突密度降低和突觸可塑性喪失是認知障礙發生的細胞基礎[35-36]。研究表明，小膠質細胞參與突觸的成熟和修剪；抑制小膠質細胞的活性可改變相關神經元的樹突重塑和長時程增強(long-term potentiation, LTP)[37-39]。

突觸的修剪與上述細胞凋亡碎片的吞噬過程類似，退化的突觸被小膠質細胞識別后，激活P2X和P2Y等嘌呤受體，進而激活一系列運動相關的胞內信號，促使細胞形成偽足，包裹退化的突觸，形成吞噬溶酶體，在細胞內完成分解過程[40-41]。

3 小膠質細胞的吞噬作用與常見神經退行性疾病

3.1 阿爾茲海默病(Alzheimer’s disease, AD)

AD是最常見的神經退行性疾病之一。Aβ沉積是AD的主要病理特征，可以引起進行性的神經認知功能下降。腦組織中Aβ肽段的堆積與斑塊的形成主要是由于Aβ蛋白產生與清除之間的不平衡所致，因此促進大腦中Aβ的清除對于減緩AD的發展具有積極作用[42-44]。

小膠質細胞的吞噬作用是大腦中Aβ清除的主要途徑之一。通過全基因組關聯分析(genome wide association studies, GWAS)，最新研究揭示了許多AD風險基因與小膠質細胞的吞噬功能密切相關[45-47]。其中，ABCA7、TREM2、CR1、APOE可以激活小膠質細胞的吞噬功能[48-50]；而CD33、INPP5D(SHIP-1)則對吞噬功能有抑制作用[51-52]。研究發現，疾病發展的不同階段小膠質細胞可能扮演著不同的角色[53-54]。在疾病發生的早期階段，正常的小膠質細胞可以通過吞噬、水解作用清除Aβ[55]。而隨著疾病進展，Aβ也通過毒性作用影響著小膠質細胞的吞噬功能[56]。在AD疾病發生后期，病理狀態下的小膠質細胞的吞噬作用使樹突功能障礙進一步惡化，吞噬瀕危的神經元[57-58]，同時通過分泌促炎細胞因子加速疾病的發展[59]。

Aβ的吞噬過程受到小膠質細胞多種膜受體的調節。有文獻報道目前已知的7個在小膠質細胞表達的受體，BECLIN-1在AD中表達下調，FcγRIIb、SCARA-1、CD36、RAGE、TREM2和CD33在AD中表達上調[60]。其中Beclin-1缺失降低小膠質細胞對Aβ的攝取[61-62]；FcγRIIb介導促進Aβ斑塊的清除[63-64]；SCARA-1可以提高小膠質細胞結合并吞噬Aβ的能力[65-66]；CD36通過PPARγ信號提高Aβ吞噬[67]；RAGE通過結合Aβ引起炎癥反應并促進淀粉樣變性[68]；TREM2作用于DAP12可在不引起炎癥反應的情況下激活小膠質細胞吞噬功能[26]；CD33與Aβ肽段內在化的降低有關[69]。這些線索提示我們，或許可以通過尋找節點基因，抑制小膠質細胞分泌促炎因子，激發吞噬功能清除Aβ，減緩AD病理進程。

3.2 帕金森病(Parkinson’s disease, PD)

PD的主要病理特征包括黑質中多巴胺能神經元變性和路易小體形成。作為路易小體的主要成分、PD的風險基因，α-突觸核蛋白(α-synuclein, α-syn)在PD發生發展中扮演重要角色[70-71]。了解α-syn在胞外清除和降解的機制對于改善PD疾病進程至關重要。

小膠質細胞在清除α-syn方面具有重要作用，小膠質細胞的吞噬能力可能取決于特定的α-syn分子類型[72-73]。研究發現，除了神經元可以釋放α-syn，小膠質細胞中同樣也有α-syn表達；在小膠質細胞中，正常水平的α-syn可能參與脂質介導細胞信號，過量表達的α-syn則會使吞噬功能受損[74-76]。在PD病人中，α-syn異常聚集；小膠質細胞快速增殖肥大，CD11b、CD68、MHC-I和 MHC- II 等標記物增多；相對其他腦區，黑質中的小膠質細胞富集，同時小膠質細胞黑質定位誘發PD患者多巴胺神經元的免疫損傷[77-79]。

注：在神經發育過程中，凋亡的神經元及未成熟的突觸被小膠質細胞識別后，激活P2X和P2Y等嘌呤受體，進而激活一系列運動相關的胞內信號，如PI3K、PKA、Src等；活化的小膠質細胞通過變形蟲樣移動，包裹退化的突觸，吞噬細胞碎片。在神經退行性疾病中，小膠質細胞通過利用多種受體，如TREM2、TLR2、TLR4、TLR9、CD36等，激活下游信號，直接或間接地促進Aβ、α-syn及其他錯誤折疊蛋白的吞噬。圖1 小膠質細胞的吞噬功能在神經發育和神經退行性疾病中的作用和分子機制Note.During neurodevelopment, apoptotic neurons and unmatured synapses are recognized by multiple purinergic P2X/P2Y receptors in microglia cells, which trigger activation of a series of motion-related intracellular signaling, such as PI3K, PKA, and Src. Activated microglia move by amoeboid-like movements and gather around the lesion, clearing cellular debris by phagocytosis. In neurodegenerative diseases, microglia activate various receptors, including TREM2, TLR2, TLR4, TLR9 and CD36, which then activate downstream signaling, promoting phagocytosis of Aβ, α-syn and other misfolding proteins directly or indirectly.Fig.1 Phagocytic function of microglia and underlying mechanism in neurodevelopment and neurodegenerative diseases

目前已知α-syn可以激活小膠質細胞上TLR、CD36等膜受體，并進一步激活NFκB、ERK1/2、p38MAPK等胞內信號[80-83]，這些研究為我們尋找PD治療靶點提供了新線索。

3.3 肌萎縮側索硬化癥(amyotrophic lateral sclerosis, ALS)

ALS是一種致命的神經退行性疾病，其病理特征為上運動神經元(大腦、腦干、脊髓)和下運動神經元(顱神經核、脊髓前角細胞)的進行性退變。目前已知SOD1、C9ORF72和TARDBP/TDP-43是ALS的三大致病基因。損傷的運動神經元及星形膠質細胞釋放錯誤折疊的mSOD1蛋白使其獲得毒性作用，可以引起氧化性損傷；而其他ALS相關蛋白，如變異的TDP- 43，可能增加運動神經元中的氧化應激[84-85]。

小膠質細胞一經激活誘發神經毒性或者神經保護作用，依賴于其激活狀態及疾病發展階段[86]。在ALS早期，小膠質細胞CD206、Ym1表達升高，呈現為吞噬功能增強，能夠促進修復及再生。隨著疾病的發展，損傷的運動神經元釋放危險信號，小膠質細胞呈現為NOX2、ROS、TNFα、IL1和 IL6等促炎因子分泌增加，產生神經毒性[87-89]。mSOD1可以激活小膠質細胞，通過CD14、TLR2、TLR4 激活下游各種清除劑受體依賴的信號通路[90-91]。死亡神經元和異常神經元在胞外釋放ATP也可激活小膠質細胞，通過P2X、P2Y誘發一系列炎癥反應[89]。此外，C9ORF72突變可以降低小膠質細胞清除聚合蛋白的能力，同時改變小膠質細胞的應答，引起神經炎癥[92]。

4 小結與展望

綜上所述，小膠質細胞的功能是多方面的，主要包括神經組織的監視功能、吞噬作用以及細胞因子、炎癥因子、趨化因子和生長因子的分泌等[93-94]。關于小膠質細胞吞噬作用的分子機制，總結如圖1。在腦組織發育、功能維持中，小膠質細胞發揮其正常生理功能；而在神經退行性疾病發生發展等病理過程中，小膠質細胞則是調節神經炎癥的主要細胞[4, 95-96]。小膠質細胞就像一把雙刃劍，一方面可以通過吞噬功能、生長因子分泌促進損傷的修復，另一方面也可以誘發神經炎癥并加深免疫損傷。值得注意的是，小膠質細胞的吞噬和活化具有不同的調節機制。不論是活化的、終末的或是靜息的小膠質細胞都具有吞噬功能，而活化的、終末的、靜息的小膠質細胞對炎癥因子和趨化因子等的分泌卻并不相同的[48, 94, 97-98]。盡管相關方向的研究較少，但這已經為解決小膠質細胞在神經疾病的發生發展過程中的“雙刃劍”問題提供了線索。尋找小膠質細胞吞噬和活化調節過程的節點基因，加深對小膠質細胞不同狀態調控的了解，通過干預使小膠質細胞向抑制疾病的方向發展，如加強吞噬作用、減弱炎癥因子分泌等，可能將是神經退行性疾病治療方法的發展方向之一。

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