凋亡细胞胞葬配体 | 巨噬细胞胞葬受体 | 桥接分子 |
---|---|---|
LPC、S1P、ATP、UTP、PS | 直接受体:G2A、S1PR、P2Y2、LRP1、SRB1、BAI1、TIM-4、RAGE、TREM2 间接受体:TAM、Integrins | Gas6、ProS、MFGE8 |
成年人体内约有37.2万亿个细胞,每天死亡的细胞约占0.4%[1]。凋亡细胞的清除效率很高,因此即使在新陈代谢很高的组织中,凋亡细胞数量也很少。吞噬细胞通过其胞葬作用参与凋亡细胞的清除,从而在维持组织稳态方面发挥重要作用。吞噬细胞胞葬功能障碍使凋亡细胞无法清除,可发生继发性坏死,导致病理性炎症和引起自身免疫反应[2]。另有研究[3]表明,吞噬细胞的胞葬作用可抑制炎症细胞因子和效应T淋巴细胞的产生,而与肿瘤的进展相关。肝脏疾病是影响全球的重要公共健康问题。据估计,我国有超过1/5的人口患有某种形式的肝病,如病毒性肝炎、非酒精性脂肪性肝病(NAFLD)、酒精性肝病、药物性肝损伤、肝硬化和肝细胞癌(HCC)等,是我国人群肝病发病率和死亡率较高的主要原因之一[4]。目前针对不同类型的肝病虽有一些相应的治疗手段,但尚不能完全满足对各种肝病治疗的需要。肝巨噬细胞是肝脏中具有胞葬功能的专职吞噬细胞[5],近年来,越来越多的证据表明肝巨噬细胞的胞葬作用与急性肝损伤、酒精性肝病、自身免疫性肝病、肝纤维化和HCC等多种急慢性肝病相关[6],是当前肝病领域研究的热点之一。本文主要从巨噬细胞与凋亡细胞胞葬相关分子的表达、胞葬过程及巨噬细胞胞葬功能在不同肝病中的作用和相关治疗等方面开展综述。
巨噬细胞的胞葬作用与经典的吞噬作用不同,其中凋亡细胞和巨噬细胞胞葬相关分子(包括胞葬配体、受体和桥接分子)的表达对巨噬细胞清除凋亡细胞至关重要(表1)。凋亡配体与巨噬细胞胞葬受体结合诱导巨噬细胞骨架重排并促进对凋亡细胞的吞噬,随后吞噬体与溶酶体融合降解凋亡细胞中的物质[7]。
凋亡细胞胞葬配体 | 巨噬细胞胞葬受体 | 桥接分子 |
---|---|---|
LPC、S1P、ATP、UTP、PS | 直接受体:G2A、S1PR、P2Y2、LRP1、SRB1、BAI1、TIM-4、RAGE、TREM2 间接受体:TAM、Integrins | Gas6、ProS、MFGE8 |
凋亡细胞胞葬配体的表达是诱导巨噬细胞对其吞噬清除的首要步骤,其主要的配体分子包括溶血磷脂酰胆碱(lysophosphatidylcholine,LPC)、鞘氨醇-1-磷酸(sphingosine-1-phosphate,S1P)、腺苷三磷酸(adenosine triphosphate,ATP)、尿苷三磷酸(uridine triphosphate,UTP)等。上述信号分子被吞噬细胞上的受体感知,诱导吞噬细胞向凋亡细胞迁移。磷脂酰丝氨酸(phosphatidylserine,PS)是凋亡细胞表达的另一种胞葬相关配体,其通过与巨噬细胞中相应的受体结合,介导巨噬细胞对凋亡细胞的摄取和吞噬[8]。
巨噬细胞胞葬受体根据与其配体的结合方式不同可分为直接受体和间接受体。其中G蛋白偶联受体(G-protein-coupled receptor,G2A)、嘌呤能受体(purinergic receptors,P2Y2)、鞘氨醇-1-磷酸受体(sphingosine-1-phosphate receptor,S1PR)可与凋亡细胞表达的LPC、ATP和UTP、S1P直接结合,从而使巨噬细胞迁移至凋亡细胞周围。而低密度脂蛋白受体相关蛋白1(low-density lipoprotein receptor related proteins 1,LRP1)、清道夫受体B1(scavenger receptor1,SRB1)、脑特异性血管生成抑制剂1(brain-specific angiogenesis inhibitor 1,BAI1)、T淋巴细胞免疫球蛋白黏蛋白受体4(T cell immunoglobulin mucin receptor4,TIM-4)、晚期糖基化终产物受体(advanced glycation end-product receptor,RAGE)和骨髓源性细胞表达的触发受体2(triggering receptor expressed in myeloid cells 2,TREM2)等则可与凋亡细胞的PS直接结合,继而诱导巨噬细胞对凋亡细胞的吞噬。间接受体是指通过桥接分子与凋亡细胞中的PS相结合,主要包括TYRO3/Axl/MER酪氨酸激酶受体(TYRO3/Axl/MER tyrosine kinase receptor,TAM)和整合素(Integrins)。巨噬细胞胞葬受体分子被激活后可触发不同的信号通路促进细胞骨架重排,完成对凋亡细胞的吞噬及随后的降解[6,8-9]。
桥接分子有2个受体结合域,在巨噬细胞和凋亡细胞之间起桥梁作用。主要的桥接分子包括生长阻滞特异性蛋白6 (growth arrest specific 6,Gas6)、蛋白S(protein S,ProS)、乳脂球表皮生长因子8(milk fat globule epidermal growth factor 8,MFGE8)等,这些桥接分子的分泌可促进巨噬细胞对凋亡细胞的吞噬和清除[10]。
巨噬细胞的胞葬过程主要分为4个阶段:(1)招募阶段。凋亡细胞表达和释放的LPC、S1P、ATP、UTP、趋化因子C-X3-C-基序配体1等信号被巨噬细胞相应的受体分子感知,招募巨噬细胞至凋亡细胞的周围。(2)识别阶段。巨噬细胞的胞葬受体如趋化因子C-X3-C-基序受体1、LRP1、TREM2等识别并结合凋亡细胞表达的PS等配体分子。(3)吞噬阶段。胞葬配体与受体结合后激活巨噬细胞Rho GTP酶(Rho GTPases)介导对凋亡细胞的吞噬。(4)降解阶段。胞葬细胞通过线粒体裂解增加吞噬小体封闭所需的胞质钙水平,并通过合成磷脂酰肌醇3,4,5-三磷酸和产生活性氧,促进LC3相关的吞噬,随后吞噬溶酶体融合、酸化,最终导致凋亡细胞的降解[7-9]。
急性肝损伤是由多种肝毒性因素如肝炎病毒、药物和免疫损伤等因素导致短时间内大量肝细胞死亡[11]。研究[12]表明,急性肝损伤时,包括TAM家族在内的多种胞葬相关受体在巨噬细胞上表达上调,巨噬细胞胞葬功能增强,在清除死亡细胞的同时,分泌一些细胞因子如IL-10、IL-4、IL-6和TNF-α等,可抑制炎症和刺激组织再生,从而有利于急性肝损伤后肝组织的修复。
IRI是肝外伤、肝部分切除术和肝移植过程中发生的一种不可避免病理结果,可损害患者的肝功能[13]。巨噬细胞的胞葬作用通过促进对死亡细胞的清除、抑制炎症反应,在IRI中发挥积极作用。研究[12]表明,MER酪氨酸激酶(mer tyrosine kinase receptor,MerTK)和Gas6信号被抑制的小鼠,其促炎细胞因子如TNF和IL-1β的mRNA水平升高,而激活巨噬细胞中的Gas6/MerTK信号通路则抑制这些细胞因子的产生,显著降低了IRI后暴发性肝衰竭发生的风险。巨噬细胞中TIM-4和TREM2受体被激活后可促进IL-10产生和Ras-related C3肉毒毒素底物1(Ras-related C3 botulinum toxin substrate 1,Rac1)的激活,促进巨噬细胞对凋亡细胞的吞噬和抑制IRI后炎症反应[14-15]。
ALF是由各种因素导致的肝细胞短期内发生广泛死亡,从而使肝脏发生无法控制的炎症反应[16]。研究[12,17-18]表明,巨噬细胞TAM受体在ALF中具有保护作用。与健康人相比,ALF患者肝脏中MerTK+巨噬细胞显著增多,通过胞葬作用清除凋亡的中性粒细胞,促进ALF后的炎症消退。其机制与肝X受体(liver X receptor,LXR)和5-脂氧合酶密切相关。巨噬细胞激活的MerTK信号除可诱导炎症抑制因子LXR丰度的恢复,还可通过细胞外调节蛋白激酶/肌质网钙泵2/钙/钙调素依赖性蛋白激酶2通路抑制5-脂氧合酶的磷酸化,促进脂素A4的合成,最终促进炎症消退。Axl是TAM受体家族中的另一个成员,Axl与Gas6结合后其细胞质内的酪氨酸残基发生磷酸化,诱导巨噬细胞自噬,抑制NOD样受体蛋白3(oligomerization domain-like receptors protein 3,NLRP3)炎性小体的激活,进而改善肝损伤。
巨噬细胞通过胞葬作用促进对死亡细胞的清除,抑制炎症反应可促进急性肝损伤的修复,但在不同类型的慢性肝病中巨噬细胞的胞葬功能可改善或推动疾病的进展,这可能与多种不同因素及复杂的分子机制有关。
酒精性肝病是由于长期饮酒导致的慢性肝脏疾病,未经有效干预,可从酒精性脂肪肝发展为酒精性脂肪性肝炎、肝纤维化和HCC[19]。巨噬细胞胞葬功能障碍在酒精性肝病的发展及相关并发症如败血症的发生中具有重要作用。(1)酒精可抑制巨噬细胞MFGE8基因的表达,影响巨噬细胞的胞葬功能,使凋亡细胞不能清除而发生继发性坏死,促炎因子释放增加,加重肝损伤。(2)酒精性肝病患者血清中高迁移率族蛋白B1表达上调,其可作为损伤相关分子模式蛋白激活促炎Toll样受体(Toll like receptor,TLR)和NLRP3信号,同时与MFGE8竞争性结合PS抑制巨噬细胞对凋亡细胞的吞噬。(3)酒精性肝病患者肠道屏障功能遭到破坏,可合并细菌感染引起的败血症。中性粒细胞浸润增加并通过形成中性粒细胞胞外陷阱(neutrophil extracellular trap,NET)使微生物死亡是控制感染的有效手段。为了抑制NET后的炎症反应,NET通过巨噬细胞的胞葬作用而清除。酒精可显著抑制肝脏NET的形成和巨噬细胞对中性粒细胞的清除,从而延长肝脏炎症和损伤。研究[20-22]表明,重组人MFG-E8通过增强巨噬细胞的胞葬功能可降低酒精相关败血症患者血清中的TNF-α、IL-6和内毒素水平,提示重组人MFG-E8在酒精性肝病及其相关败血症的治疗方面可能具有较好的疗效。
NAFLD是常见的慢性肝脏疾病之一,脂肪积累和炎症是NAFLD进展的主要原因,根据病变的严重程度可分为非酒精性脂肪肝(NAFL)和非酒精性脂肪性肝炎(NASH)[23-24]。超重及肥胖是NAFLD发生重要因素,而巨噬细胞的胞葬功能障碍可促进NASH的发展,胞葬受体TREM2的表达对巨噬细胞吞噬清除凋亡细胞具有重要作用。长期高营养状态可导致肝脏促炎因子如TNF、IL6和IL-1β的产生,这些炎症细胞因子通过解聚素金属蛋白酶17(a disintegrin and metalloprotease 17,ADAM17)依赖的方式诱导TREM2脱落,TREM2的表达下调导致巨噬细胞的胞葬功能减弱,凋亡的肝细胞异常积累,炎症细胞因子产生增加,促进NAFL向NASH方向进展。因此,靶向ADAM17的抑制剂或TREM2的激动剂可能是NAFLD的潜在治疗靶点[25]。
自身免疫性肝病是以自身抗体产生为主要特征的慢性肝病,主要包括自身免疫性肝炎、原发性胆汁性胆管炎及原发性硬化性胆管炎[26]。在自身免疫性肝病中,细胞凋亡是肝细胞和胆管上皮细胞死亡的主要方式,而巨噬细胞对凋亡细胞的清除障碍与自身免疫性肝病的发生相关[6,27]。巨噬细胞的胞葬相关受体如TIM、Axl和MerTK等表达下调导致其胞葬功能减弱,凋亡细胞不能被清除而发生继发性坏死,导致自身抗原成分和炎症细胞因子释放,继而吸引免疫攻击,促进疾病进展。此外,巨噬细胞胞葬功能障碍除了可促进炎症细胞因子释放激活肝星状细胞外,还可同抑制多种基质金属蛋白酶的产生而促进肝纤维化的发生,使自身免疫性肝病朝不可逆的方向发展[28-29]。靶向巨噬细胞TIM、Axl、MerTK的激动剂的增强巨噬细胞胞葬作用可能为自身免疫性肝病开辟新的治疗前景。
肝纤维化是各种慢性肝病的晚期阶段,可进展为肝硬化、HCC,严重影响患者的生存质量[30]。巨噬细胞的胞葬功能在肝纤维化中的作用是具有争议的。巨噬细胞表达的stabilin-1与PS及丙二醛低密度脂蛋白结合可促进对凋亡细胞的清除,抑制促纤维化因子产生,从而对肝纤维化的发生起到积极的保护作用[5]。TIM-4是巨噬细胞表达的另一个胞葬相关受体,也可抑制肝纤维化的发生,其机制主要包括:(1)TIM-4与TAM受体协同作用促进巨噬细胞对凋亡肝细胞的清除,抑制肝细胞线粒体损伤相关分子模式蛋白的释放和肝星状细胞的激活;(2)TIM-4与PS结合激活LKB1/AMPKα信号通路抑制NLRP3炎症小体,减少促炎细胞因子的释放,从而起到抑制肝纤维化的作用[12]。与此相反的是,巨噬细胞中MerTK的表达可通过细胞外调节蛋白激酶1/2途径使TGF-β产生增加,继而激活肝星状细胞而对肝纤维化发生具有促进作用。研究[31]表明,全反式维甲酸通过激活ADAM17裂解MerTK分子可抑制TGF-β的产生,故其可能是肝纤维化的潜在治疗靶点。
HCC是肝恶性肿瘤之一,也是多种慢性肝病的终末期形式。HCC患者的预后较差,长期生存率较低[32]。巨噬细胞胞葬分子的表达与HCC的进展密切相关。巨噬细胞PS受体激活将干扰NF-κB信号传导和Ⅰ型干扰素的产生,进而限制抗肿瘤免疫反应。在HCC中,MerTK+巨噬细胞在清除凋亡的肿瘤细胞时可产生免疫抑制因子如IL-13和TGF-β等,使免疫系统沉默,促进肿瘤细胞逃脱免疫监视和攻击[33-35]。由在肿瘤生长、血管生成和转移中的作用,针对PS及其受体TIM、TAM阻断性抗体正成为抗肿瘤治疗的研究热点。例如,新型抗TIM3抗体与抗PD1抗体的联合可用于HCC的治疗[36]。研究[5]证实,HCC细胞通过上调“非吃我信号”CD47分子的表达,可阻止巨噬细胞对其识别,通过阻断CD47与巨噬细胞信号调节蛋白α1的相互作用,增强巨噬细胞对肿瘤细胞的吞噬,可抑制HCC的进展。综上所述,巨噬细胞和HCC细胞胞葬分子的表达可通过抑制免疫反应、阻碍巨噬细胞对肿瘤细胞的识别而促进HCC的进展。
近年来,越来越多的证据表明巨噬细胞的胞葬功能与多种肝病密切相关,但其机制尚未完全明确。巨噬细胞的胞葬功能在不同类型肝病中的作用不同。一方面,巨噬细胞的胞葬功能障碍可能促进酒精性肝病、非酒精性肝病及自身免疫性肝病的进展;另一方面,巨噬细胞的胞葬作用可能在肝纤维化、HCC的进展中具有”双刃剑”效应,这可能与巨噬细胞胞葬受体的冗余性有关。凋亡配体与不同受体的结合可能通过不同的信号通路而产生不同的效果。深入研究巨噬细胞胞葬分子在不同肝病的表达情况及分子机制,开发靶向多种胞葬分子的药物,有望使更多肝病患者受益。
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凋亡细胞胞葬配体 | 巨噬细胞胞葬受体 | 桥接分子 |
---|---|---|
LPC、S1P、ATP、UTP、PS | 直接受体:G2A、S1PR、P2Y2、LRP1、SRB1、BAI1、TIM-4、RAGE、TREM2 间接受体:TAM、Integrins | Gas6、ProS、MFGE8 |