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   复旦学报(医学版)  2020, Vol. 47 Issue (6): 911-916      DOI: 10.3969/j.issn.1672-8467.2020.06.018
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巨噬细胞对凋亡细胞的清除及炎症调控作用
谭海鹏1,2  (综述), 黄浙勇1,2  (审校)     
1. 复旦大学附属中山医院心内科 上海 200032;
2. 上海市心血管病研究所 上海 200032
摘要:胞葬作用(efferocytosis)是机体内凋亡细胞被吞噬细胞清除的生理过程,而巨噬细胞是一种重要的吞噬细胞。炎症是机体防御感染及修复损伤的保护性反应,但过度强烈的炎症和持续的慢性炎症则与许多疾病的发生和发展密切相关。巨噬细胞不仅可以通过对凋亡细胞的吞噬来避免炎症的发生,还可以通过在胞葬过程中与凋亡细胞及其代谢产物之间的相互作用获得主动性的抗炎效应。这一抗炎效应对炎症的及时消退及组织损伤后修复和再生过程的启动都至关重要。本文就近年来的研究进展对胞葬作用抗炎效应的产生机制进行综述。
关键词凋亡细胞    巨噬细胞    胞葬作用    炎症调控    机制    
Clearance of apoptotic cells by macrophages and resolution of inflammation
TAN Hai-peng1,2 , HUANG Zhe-yong1,2     
1. Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China;
2. Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China
Abstract: Efferocytosis is a physiological process in which apoptotic cells are cleared by phagocytes, and macrophages are one of the most important members of these phagocytes.Inflammation is a protective response of the body against infection and tissue damage, but excessive inflammation and persistent chronic inflammation are closely related to the occurrence and development of many diseases.Macrophages can not only avoid the occurrence of inflammation through the phagocytosis of apoptotic cells, but also obtain an active anti-inflammatory effect by interacting with apoptotic cells and their metabolites during this process.This active anti-inflammatory effect is essential for the timely resolution of inflammation and critical for the initiation of repair and regeneration after tissue damage.This review summarizes the recent research progress related to the mechanism of this active anti-inflammatory effect.
Key words: apoptotic cells    macrophages    efferocytosis    immunomodulation    mechanism    

凋亡(apoptosis)是组织器官发生发育、组织细胞更新、疾病发生发展等生理和病理过程中细胞死亡的主要形式之一,而机体内凋亡的细胞主要通过胞葬作用(efferocytosis)被以巨噬细胞为主的吞噬细胞清除[1]。凋亡细胞的有效清除对维护机体内环境的稳态至关重要,而凋亡细胞清除障碍已经被证实与免疫系统异常应答、动脉粥样硬化等多种疾病的发生发展密切相关[2]

自1998年Henson等[3]首次报道胞葬作用可以产生主动性抗炎效应以来,细胞凋亡、胞葬作用和炎症反应之间的关系一直备受关注。研究证实,在防御感染和修复损伤的急性炎症反应中,凋亡的局部组织细胞或凋亡的炎症细胞与巨噬细胞之间的相互作用,对于抑制炎症反应的进一步放大和促进炎症及时消退至关重要[4]。因此,胞葬作用的抗炎效应为积极干预反应过强、持续过久的炎症提供了新的可能,但其产生的机制尚不完全清楚。本文就近年来的研究进展,对胞葬作用抗炎效应的产生机制进行综述。

胞葬过程简述  胞葬作用是凋亡细胞和吞噬细胞之间相互适应、相互协调的生理过程,主要包括招募、识别、吞噬等3个阶段。胞葬作用的信号网络系统主要由“find me”、“keep out”、“eat me”以及“do not eat me”信号等4个部分构成[5]

招募阶段  细胞在发生凋亡时,会合成和释放一系列“find me”信号分子,主要包括溶血卵磷脂(lysoph-osphatidylcholine,LysoPC)、鞘氨醇-1-磷酸(sphingosine-1-phosphate,S1P)、趋化因子CX3CL1(fractalkine)、核苷酸ATP/UTP[6]。这些凋亡信号分子通过细胞外液传递给定植于其周边的巨噬细胞,或经过血液循环传递给骨髓、脾脏等组织中的单核细胞,分别被这些吞噬细胞表面的G蛋白偶联受体G2A家族(G2A family of G-protein-coupled receptors,G2A)、鞘氨醇-1-磷酸受体(sphingosine-1-phosphate receptor,S1PR)、趋化因子受体CX3CR1和G蛋白偶联受体P2Y家族(P2Y family of G-protein-coupled receptors,P2Y)识别后,将吞噬细胞趋化到凋亡细胞所在的组织区域,实现招募过程[5, 7]。与此同时,凋亡细胞还会分泌“keep out”信号来排斥粒细胞等其他炎症细胞的募集,达到选择性趋化单核细胞和巨噬细胞的目的。乳铁蛋白(lactoferricin)是目前唯一认识明确的“keep out”信号[8]

识别阶段  细胞凋亡过程中,仅存在于活细胞膜内表面的磷脂酰丝氨酸(phosphatidyl serine,PS)通过半胱/天冬氨酸蛋白酶级联反应依赖的方式外翻到细胞外表面,成为凋亡细胞表面最主要的“eat me”信号分子[9]。巨噬细胞可通过其膜表面的脑特异性血管生成抑制因子(brain-specific angiogenesis inhibitor,BAI)、T细胞免疫球蛋白黏蛋白受体4(T cell immunoglobulin mucin receptor 4,TIM4)、清道夫受体stabilin2和髓样相关免疫球蛋白受体CD300f等跨膜受体直接识别并结合PS;其也可通过分泌生长停滞特异因子6(growth arrest specific 6,Gas6)和蛋白S(protein S,PROS)作为桥梁分子,介导其膜表面的酪氨酸激酶受体家族(TYRO3、AXL、MERTK,即TAM)对PS的识别;还可通过以牛乳脂球表皮生长因子8(milkfat globuleepidermal growth factor 8,MFGE8)或补体成分C1q作为桥梁分子,实现整合素受体家族αvβ系列受体对PS识别,进而启动后续的吞噬过程[5, 10-11]。其他的“eat me”信号还包括细胞间黏附因子3(intercellular adhesion molecule 3,ICAM3)、钙网蛋白(calreticulin)、氧化低密度脂蛋白(oxidized low density lipoprotein,ox-LDL)、糖基化蛋白等[5]。PS虽然是凋亡细胞的重要标志之一,但少数生理状态下的活细胞也会有PS的外翻,而活细胞主要通过其表面的CD47和CD31等“do not eat me”信号与巨噬细胞表面相应受体分子间的相互作用来抑制巨噬细胞对自身的清除[5]

吞噬阶段  巨噬细胞对来自凋亡细胞的各种信号进行整合处理后,汇集到ELMO1/Dock180和GULP1这两条吞噬信号通路,继而激活进化上高度保守的一种GTP酶Rac1,胞葬进入吞噬阶段[12]。活化后的Rac1形成吞噬环,最终通过Scar/WAVE复合体促进肌动蛋白聚合和细胞骨架的重排,完成对凋亡细胞的吞噬过程[13]

巨噬细胞的活化和极化  巨噬细胞在各种局部微环境不同刺激物的作用下,主要通过三大信号通路活化,并最终分化为经典活化型巨噬细胞(即M1)和替代活化型巨噬细胞(即M2)。这三大信号通路分别为:转录因子核因子κB(nuclear factor-κB,NF-κB)、激活剂蛋白1(activator protein1,AP-1)和干扰素调节因子(interferon regulatory factor,IRF)相关信号通路,信号转导子及转录激活子(signal transducer and activator of transcription,STAT)相关信号通路和核受体相关信号通路[14]

转录因子NF-κB/AP-1/IRF相关信号通路  巨噬细胞内转录因子NF-κB/AP-1/IRF相关信号通路主要接受Toll样受体家族(Toll-like receptors,TLRs)、肿瘤坏死因子受体(tumor necrosis factor receptor,TNFR)和IL-1受体(IL-1 receptor,IL-1R)的信号转入[15-16]。3个受体家族被相应的配体激活后,通过下游的酶联反应,活化转录因子NF-kB、AP-1和IRF,调控巨噬细胞活化和极化相关基因的表达[16]。NF-κB主要以异二聚体或同源二聚体结构发挥作用,主要包括p65和p50亚基。其中p50是促进M2极化的关键分子,而p65则是巨噬细胞向M1极化的标志之一[17]

转录因子STAT相关信号通路  巨噬细胞内转录因子STAT上游的受体主要包括Ⅰ型干扰素受体(type Ⅰ IFN receptor,IFNAR)、Ⅱ型干扰素受体(IFNBR)和IL-4R[18]。这些受体下游通路中主要的STAT家族成员是STAT1/3/6,其中STAT1/3主要促进巨噬细胞炎症因子表达及其向M1极化,而STAT6则可调控多种M2标志物基因表达,是促进巨噬细胞向M2极化的核心转录因子[18-20]

核受体相关信号通路  巨噬细胞胞内的核受体被相应的脂类信号激活后,也会影响巨噬细胞状态和功能[21]。识别凋亡细胞降解产物的核受体主要包括氧化物酶体增殖物激活受体(peroxisome proliferator activated receptor,PPAR)、肝X受体(liver X receptor,LXR)、维生素D受体(vitamin D receptor,VDR)和维甲酸类受体(retinoic acid receptor,RR),其中RR包括RAR和RXR两种亚型[5]。巨噬细胞吞噬并降解凋亡细胞后产生的代谢产物作用于巨噬细胞胞内的核受体,可直接调控相关基因的表达,也可通过与胞内其他信号转导通路之间的相互调节发挥作用[22]

胞葬作用主动抗炎效应的产生机制  胞葬过程中,巨噬细胞膜表面或基质内凋亡信号识别受体被激活,其下游信号通路中的效应分子活化;通过与巨噬细胞活化和极化相关信号通路中的信号分子之间的相互作用,这些效应分子可以影响巨噬细胞的状态和功能(图 1)。

图 1 胞葬作用主动抗炎效应的产生机制 Fig 1 Mechanism of active anti-inflammatory effect of efferocytosis

胞葬作用调控转录因子NF-κB/AP-1/IRF相关信号通路  在转录因子NF-κB/AP-1/IRF相关信号通路的级联反应中,TNFR相关因子3/6(TNFR associated factor 3/6,TRAF3/6)、转化生长因子-β-活化蛋白激酶1(transforming growth factor-β-activated kinase 1,TAK1)、髓样分化因子适配蛋白(MyD88-adaptor-like protein,MAL)、转录因子NF-kB的亚基P65和凋亡信号调节激酶1(apoptosis signal regulating kinase 1,ASK1)等关键分子都是胞葬作用调控巨噬细胞活化和抑制其向M1极化的介入节点。巨噬细胞TAM受体被凋亡细胞表面的PS活化后,通过STAT相关信号通路上调细胞因子信号转导抑制因子(suppressor of cytokine signaling,SOCS)的表达[23]。值得注意的是,转录因子NF-κB/AP-1/IRF相关信号通路的激活是促进TAM受体和SOCS表达上调的始动因素,而PS对TAM受体的活化使巨噬细胞内SOCS的表达量增加10倍以上,形成一个正反馈效应[24]。SOCS具有泛素连接酶活性,通过识别目标蛋白并促进其泛素化降解而发挥作用[25]。SOCS家族共有SOCS1~7和CIS等8个成员,目前研究较为深入的是SOCS1和SOCS3[26]。通过SOCS1促进MAL、ASK1和P65降解,以及SOCS3促进TRAF3/6、TAK1降解,巨噬细胞内NF-κB/AP-1/IRF相关信号通路受到全方位的抑制,其炎症因子的表达水平下调,M1极化相关基因的表达也明显降低[24]

胞葬作用调控转录因子STAT相关信号通路  转录因子STAT相关信号通路中共有的Janus蛋白激酶(Janus kinase,JAK)是胞葬作用调控巨噬细胞活化和极化的又一个重要靶点。PS通过桥梁分子Gas6和PROS间接激活TAM后,表达上调的SOCS1和SOCS3均可促进JAK的泛素化降解,而SOCS3则可促进STAT1/3的降解,从而降低巨噬细胞炎症因子的表达并抑制其向M1的极化[26]。SOCS对JAK-STAT6通路的调控是否会抑制巨噬细胞向M2的极化尚存在争议。

胞葬作用调控核受体相关信号通路  巨噬细胞吞噬凋亡细胞后产生的维甲酸类代谢产物:如全反式维甲酸(all-trans retinoic acid,ATRA)和顺式维甲酸(cis-retinoic acid,CRA),作用于RAR和RXR会抑制TNF-α、可诱导型一氧化氮合酶(inducible nitric oxide synthase,iNOS)和IL-12等炎症因子的表达,同时促进TGF-β和IL-10等炎症抑制因子的产生[27]。具体机制可能与维甲酸类受体对转录因子STAT相关信号通路的调控作用有关[28]。巨噬细胞胞内维甲酸类受体活化后,可通过促进纤溶酶原激活物抑制剂2(tissue-type plasminogen activator inhibitor 2,t-PAI2)的表达来抑制炎症部位细胞外基质的蛋白水解作用,从而减少炎症带来的组织损伤[29]。此外,还有报道称ATRA可促进M1向M2转化,但其具体机制作者并未进行深入的探索[30]。PPAR家族主要包括α、β和γ等3种亚型,参与胞葬作用抗炎效应的主要是是PPAR-γ[31]。凋亡细胞降解后产生的不饱和脂肪酸、氧化低密度脂蛋白衍生物、溶血磷脂、5-羟色胺衍生物及脱氧前列腺素等代谢产物激活巨噬细胞胞内的PPAR-γ,可显著抑制巨噬细胞炎症因子的表达[5, 32]。研究表明,PPAR-γ活化后不仅直接调控基因表达,还可通过对转录因子AP-1、NF-kB、STAT相关信号通路的阻断来实现抗炎效应,但其具体作用节点尚不清楚[31]。还有报道称,PPAR-γ受体活化后,可通过与JAK1-STAT6通路间的相互作用,促进巨噬细胞向M2极化,具体机制有待进一步研究[33-34]。凋亡细胞降解产物中的胆固醇及其各种衍生物激活LXR后,可以直接抑制巨噬细胞内环氧化酶2(cyclooxygenase 2,COX-2)、iNOS和IL-6等炎症因子的产生;可以通过与STAT1相关信号通路的相互作用促进抗炎因子的表达;还可以上调巨噬细胞表面PS识别受体MERTK的表达量,进一步促进巨噬细胞对凋亡细胞的清除[11, 35-37]。凋亡细胞降解产物激活VDR后,也可直接入核或通过与NF-κB相关信号通路相互作用,调控炎症因子表达和巨噬细胞活化,并阻断炎症因子下游效应通路[38-39]。总的来说,核受体直接入核调控抗炎因子表达在胞葬作用抗炎效应中的作用较为确切,而核受体相关信号通路与其他信号通路之间的相互作用仍有待进一步阐明。

胞葬作用调控其他信号通路  TIM4在识别并结合PS结合后,可通过激活一种非典型自噬通路,下调促炎因子表达水平的同时,促进抗炎因子的表达[40-41]。活化的CD300f可通过与IL-4R之间的协同作用,增强巨噬细胞对IL-4的反应性,从而促进巨噬细胞向M2极化[42]

结语  随着胞葬作用分子基础的进一步阐明,我们对胞葬作用抗炎效应的研究也有了越来越多的着手点。胞葬作用可通过调控巨噬细胞活化和向M1极化的信号通路,下调炎症因子的表达和抑制其向M1的极化,具有显著的炎症负向调控作用。但胞葬作用是否可通过促进巨噬细胞向M2极化来实现抗炎效应仍有待进一步探索。深入研究胞葬作用抗炎效应的产生机制,有助于理解细胞凋亡的生理意义,也可以为干预反应过强、持续过久的炎症提供更多新的靶点。

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文章信息

谭海鹏, 黄浙勇
TAN Hai-peng, HUANG Zhe-yong
巨噬细胞对凋亡细胞的清除及炎症调控作用
Clearance of apoptotic cells by macrophages and resolution of inflammation
复旦学报医学版, 2020, 47(6): 911-916.
Fudan University Journal of Medical Sciences, 2020, 47(6): 911-916.
Corresponding author
HUANG Zhe-yong, E-mail:zheyonghuang@126.com.
基金项目
国家自然科学基金面上项目(81870269)
Foundation item
This work was supported by the General Program of National Natural Science Foundation of China(81870269)

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