类风湿关节炎(rheumatoid arthritis, RA)是一种以慢性滑膜炎为主要特征的自身免疫病, 最终导致关节进行性损害, 甚至功能丧失[1]。巨噬细胞是RA发生发展中非常重要的效应细胞, 与多种细胞相互作用[如T、B细胞和成纤维样滑膜细胞(fibroblast-like synovial cells, FLS)等]产生大量炎性细胞因子, 导致血管翳形成, 骨和软骨破坏[2]。巨噬细胞一直被认为主要有两种不同的表型:经典活化的M1型巨噬细胞(促炎作用)和选择性活化的M2型巨噬细胞(抗炎作用), 但近年来学者们通过确切的标记发现了具体的巨噬细胞, 如CX3CR1+滑膜衬里层巨噬细胞[3]。RA滑膜巨噬细胞(synovial macrophages, SM)是关节滑膜中的巨噬细胞, 在炎症反应中起重要作用。最近研究发现, SM至少有两个起源, 即胚胎来源的滑膜巨噬细胞(embryonic synovial macrophages, ESM)和骨髓来源的滑膜巨噬细胞(bone marrow synovial macrophages, BMSM), ESM分泌白细胞介素-4 (interleukin-4, IL-4)和IL-10具有抗炎作用, BMSM分泌IL-1β和肿瘤坏死因子-α (tumor necrosis factor-α, TNF-α)具有促炎作用[4]。在RA关节中巨噬细胞增多, 需要更多能量发挥其功能, 导致葡萄糖代谢从氧化磷酸化转变为糖酵解、胆碱摄取增加、氨基酸和脂质代谢异常, 进而引起柠檬酸和琥珀酸等中间代谢物累积, 参与RA病理进程。本文综述了巨噬细胞在RA中的异常代谢以及以调控巨噬细胞的药物在RA治疗中的应用。
1 巨噬细胞异常代谢在RA中的作用近年来, 细胞代谢在疾病中的重要性逐渐引起人们的重视。代谢产物的复杂性和控制代谢的酶一直是了解代谢途径的主要挑战。研究表明, RA患者关节巨噬细胞增多, 导致细胞需氧量增加, 引起滑膜内供氧不足, 引发氧化应激、生物能量学改变, 进一步导致巨噬细胞代谢功能的异常[5, 6] (图 1)。
糖酵解过程中生成的丙酮酸分子在线粒体中被转化为乙酰辅酶A, 乙酰辅酶A进入三羧酸(tricarboxylic acid, TCA)循环, 最终生成36分子ATP。虽然糖酵解产生的ATP没有氧化磷酸化过程产生的多, 但是其速度远远快于氧化磷酸化[7]。RA中M1巨噬细胞的糖代谢主要表现为糖酵解[8], 而M2巨噬细胞主要为氧化磷酸化。Anthony等[9]发现大多数RA患者关节SM大量表达低氧诱导因子-1α (hypoxia inducible factor 1α, HIF-1α), 而健康志愿者关节滑膜中无HIF-1α的表达。HIF-1α是糖酵解的重要调节分子, HIF-1α与RA血管生成、滑膜炎症、软骨降解和骨侵蚀密切相关。RA关节滑膜中的低氧环境会激活磷脂酰肌醇激酶3 (phosphoinositide 3-kinase, PI3K)/AKT/HIF-1α通路, 诱导HIF-1α表达增加, 刺激SM和滑液巨噬细胞分泌血管内皮生长因子(vascular endothelial growth factor, VEGF), 从而促进血管生成, 加重滑膜增生。同时低氧环境和HIF-1α激活葡萄糖转运体1 (glucose-transporter-1, GULT1), 促进巨噬细胞对葡萄糖摄取和糖酵解通量增加, 导致线粒体应激和活性氧簇(reactive oxygen species, ROS)产生, IL-1β和TNF-α增多, 这些炎性因子又可上调HIF-1α的表达, 进一步引起滑膜炎症和软骨、骨损伤[5, 10]。PI3K、丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)和钙调素依赖性蛋白激酶Ⅱ (Ca2+/Calmodulin-dependent kinase II, CaMK II)通路都可调控HIF-1α活性, PI3K抑制剂LY294002已被证明能显著降低RA患者滑液巨噬细胞和THP-1巨噬细胞株中HIF-1α表达, 降低巨噬细胞分泌VEGF、IL-8和基质金属蛋白酶9[11]。在K/BxN血清转移诱导的关节炎模型中, HIF-1α基因敲除的关节炎小鼠关节巨噬细胞浸润和血管翳形成减少, 足爪肿胀程度减轻[12]。RA患者外周血和滑液单核细胞和巨噬细胞中α-烯醇化酶(α-enolase, ENO1)表达增加。ENO1是糖酵解途径磷酸甘油转化为烯醇式丙酮酸的催化酶, 可作为抗原与胶原诱导关节炎模型(collagen induced arthritis, CIA)小鼠滑液中的巨噬细胞表面的抗ENO1抗体相互结合, 通过p38MAPK和NF-κB通路刺激巨噬细胞产生TNF-α、IL-1α/β, IFN-γ和前列腺素E2 (prostaglandin E2, PGE2)[13]。另有研究发现RA患者滑液巨噬细胞含有大量糖酵解酶丙酮酸激酶M2 (pyruvate kinase M2, PKM2), 随着巨噬细胞对葡萄糖摄取的增加, PKM2二聚化进入细胞核, 磷酸化转录因子STAT3, 诱导巨噬细胞极化为M1巨噬细胞, 分泌IL-6和IL-1β, 参与RA的病理发展[14]。
研究表明, RA患者滑液M1巨噬细胞中TCA循环受阻, 异柠檬酸脱氢酶(isocitrate dehydrogenase, IDH)活性降低, 导致柠檬酸盐和衣康酸水平增加。柠檬酸盐积累可用于产生NO、ROS和PG三种重要介质, 促进M1巨噬细胞分泌炎性细胞因子[15]。衣康酸作为抗炎因子, 发挥抑制HIF-1α的作用[16]。研究[8, 17]发现RA患者滑液中琥珀酸脱氢酶(succinate dehydrogenase, SDH)活性下降导致琥珀酸水平增加。RA患者滑液含有各种内源性Toll样受体配体, 局部激活巨噬细胞, 导致糖酵解增强和巨噬细胞内琥珀酸增加, 促进HIF-1α活化, 诱导巨噬细胞活化产生IL-1β; 同时部分琥珀酸释放到巨噬细胞外, 与琥珀酸受体SUCNR1/GPR91结合, 进一步促进IL-1β产生, 加重炎症反应。CIA小鼠关节滑液中琥珀酸水平与小鼠的足爪肿胀程度有关。在抗原诱导的关节炎(antigen-induced arthritis, AIA)小鼠模型中, 基因敲除SUCNR1的小鼠膝关节肿胀程度明显减轻[18]。
1.2 胆碱代谢胆碱是细胞膜磷脂和乙酰胆碱的前体, 通过特定的转运体吸收并由胆碱激酶(choline kinase, Chok)代谢, 转化为磷脂酰胆碱。Beckmann等[19]分析了RA患者有机阳离子转运体(organic cation transporter, OCT)、胆碱转运体样(choline transporter-like, CTL)家族成员和高亲和力胆碱转运体(high-affinity choline transporter, ChT1)以及囊泡乙酰胆碱转运体(vesicular acetylcholine transporter, VACht)等经典神经元组分在人髋关节和膝关节滑膜和软骨中的表达。研究表明, OCT1、OCT3和CTL1~5蛋白在人关节的滑膜组织和软骨中均有表达, 且RA-SM中高表达CTL1。研究发现, RA患者滑液中总磷脂含量明显增加。RA中活化的巨噬细胞对胆碱有特殊的亲和力, 对胆碱摄取增强, Chok磷酸化胆碱, 产生磷脂, 同时诱导巨噬细胞产生炎性细胞因子[20, 21]。Chok对胆碱的摄取、动员、磷酸化至关重要[22-24]。在K/BxN小鼠模型中, Chok抑制剂MN58b降低小鼠关节滑液中磷脂和IL-1β的水平, 减轻关节炎症和软骨破坏[23]。体外用骨髓诱导巨噬细胞(bone marrow-derived macrophage, BMDM)研究表明, 当胆碱或Chok受到抑制后, 会导致线粒体损伤, ATP合成酶活性和细胞内ATP降低, 随后激活腺苷酸活化蛋白激酶, 促进巨噬细胞有丝分裂, 抑制巨噬细胞产生IL-1β[20]。
1.3 氨基酸代谢氨基酸不仅是蛋白质合成的基石, 也是构成关键细胞信号通路的基石。研究发现, RA巨噬细胞需要丝氨酸代谢产生谷胱甘肽来调节IL-1β的转录[25]。高通量代谢谱研究表明谷氨酰胺代谢是M2巨噬细胞的一个特征。TCA循环中几乎三分之一的碳都来自谷氨酰胺[8]。精氨酸是RA巨噬细胞代谢重要氨基酸, 是精氨酸酶(arginase, Arg)和一氧化氮合酶(nitric oxide synthase, NOS)的底物[26]。RA患者血清中Arg含量和活性升高[27]。M1巨噬细胞优先过表达NOS, 并利用精氨酸产生NO, NO过量反过来增加巨噬细胞的细胞毒性作用。相反, M2巨噬细胞优先大量表达Arg以产生鸟氨酸, 鸟氨酸是多胺的前体, 其有助于巨噬细胞增殖和恢复组织内稳态[26]。RA滑膜富含L型氨基酸转运体基因(L-amino acid transporter 1, LAT1), RA患者外周血单核细胞和巨噬细胞中LAT1表达明显升高, 介导支链氨基酸亮氨酸内流, LAT1通过哺乳动物雷帕霉素靶蛋白复合体1诱导的糖酵解重编程促进RA单核细胞和巨噬细胞分泌IL-1β和TNF-α[28]。Papathanassiu等[29]用CIA小鼠模型和BMDM发现, 支链转氨酶1 (branched-chain aminotransferases, BCAT1)是支链氨基酸分解代谢的酶, BCAT1抑制剂ERG 240可降低巨噬细胞耗氧量和糖酵解速率, 抑制炎症巨噬细胞浸润, 减轻CIA关节炎的严重程度。
1.4 脂质代谢流行病学、临床和实验室研究表明, RA巨噬细胞脂质代谢异常易引起心血管疾病如动脉粥样硬化[30, 31]。RA患者动脉粥样硬化的特点是泡沫细胞在动脉内膜层的累积, 而巨噬细胞内胆固醇的累积会形成泡沫细胞。Kiss等[32]发现RA患者血清中IL-34明显升高, 导致巨噬细胞对胆固醇摄取增加, 随后通过p38MAPK信号通路上调CD36表达, 促进泡沫细胞形成。Wen等[33]在CIA模型中检测到腹腔巨噬细胞和外周血巨噬细胞中胆固醇增加, 且细胞内清道夫受体CD36表达增加。使用辛伐他汀治疗后, 小鼠血清中高密度脂蛋白和氧化低密度脂蛋白水平降低, 从而减少了巨噬细胞内脂质累积和CD36表达。脂肪酸代谢是一个动态的合成与分解过程, 维持机体能量平衡。在许多疾病中, 这种动态平衡被破坏, 导致脂质积累[27]。脂肪酸氧化(fatty acid oxidation, FAO)对巨噬细胞在TCA循环中至关重要[34]。RA中M1巨噬细胞脂肪酸(fatty acid, FA)合成增加[8]。M2巨噬细胞FA摄取和FAO加强, 但在RA中具体机制有待于进一步研究。研究表明, IL-4和IL-13增加巨噬细胞过氧化物酶体增殖物激活受体γ共激活因子1β的表达, 导致线粒体呼吸链蛋白表达增加, 加快FAO[16, 35]。FAO生成的乙酰辅酶A又可导致胆固醇累积, 从而增加动脉粥样硬化的风险。
2 调控巨噬细胞的药物在RA治疗中的作用目前治疗RA的主要药物有改善病情抗风湿药(disease-modifying antirheumatic drug, DMARDs)、甾体抗炎药、非甾体抗炎药和天然药物。DMARDs包括传统DMARDs和生物制剂, 靶向JAK/STAT信号通路的多个小分子药物, 近年来也被研发应用于RA的临床治疗[36]。但目前还没有靶向巨噬细胞的药物, 有些药物在发挥作用的同时可以间接地影响巨噬细胞功能。传统DMARDs为一线药物, 最常见的是甲氨蝶呤, 通过抑制NF-κB和NLRP3/Caspase-1通路, 抑制巨噬细胞增多和分泌炎性细胞因子, 干扰巨噬细胞脂质代谢, 减轻关节炎症反应和骨破坏, 是大多数RA患者的首选药物[37]。
研究表明, RA患者滑膜液中性粒细胞-巨噬细胞集落刺激因子(granulocyte-macrophage colony stimulating factor, GM-CSF)及其受体表达升高, GM-CSF激活巨噬细胞、中性粒细胞和树突状细胞发挥促炎作用[38]。目前GM-CSF抑制剂(MOR103[39]、MORAb002、KB003和namilumab[40])以及抗GM-CSFRα的抗体(mavrilimumab)[41]已完成Ⅱ期临床试验[35], 对传统DMARDs耐受的患者有良好的有效性和安全性。巨噬细胞是TNF-α、IL-1和IL-6等促炎细胞因子的主要来源细胞。靶向TNF-α (etanercept、infliximab、adalimumab、certolizumab和golimumab)[42]、IL-1β (canakinumab和anakinra)[43]和IL-6 (tocilizumab、sarilumab、clazakizumab和ALX-0061)[44]的抑制剂, 通过抑制巨噬细胞极化为M1巨噬细胞, 促进单核细胞和炎性巨噬细胞的凋亡来有效控制RA滑膜炎。酪氨酸激酶抑制剂imatimb[45]和mastinib[46]也可以抑制巨噬细胞产生TNF-α, 缓解全身炎症。早期研究发现, RA组织中巨噬细胞高表达趋化因子受体1 (CC chemokine receptor 1, CCR1), CCR1拮抗剂CCX354-C能调节单核细胞和巨噬细胞向滑膜组织迁移, 减少炎性巨噬细胞浸润, 缓解关节炎症, 目前CCX354-C在临床上具有一定的安全性和有效性[47]。小分子JAK抑制剂的研究可阻止滑膜内STAT转录因子的激活, 如tofacitinib (JAK1/3抑制剂)[48]和baricitinib (JAK1/2抑制剂)[49]抑制巨噬细胞活化和产生IL-6、TNF-α等促炎细胞因子, 有效阻断RA炎症的级联反应。Peficitinib (JAK2抑制剂)[50]、upadacitinib (JAK1抑制剂)也已用于临床[51]。与tofacitinib具有类似作用机制的filgotinib正在进行Ⅲ期临床试验, 有良好的有效性[52]。
对于天然药物, 白芍总苷可通过上调Arg-1的产生和活性来抑制M1巨噬细胞的活性, 同时增强M2巨噬细胞的功能, 抑制巨噬细胞分泌IL-1β、IL-6、TNF-α、IL-8、PGE2和环氧合酶-2缓解RA关节炎症和骨破坏[53]。雷公藤中的雷公藤总苷被认为是治疗RA的主要活性成分, 抑制巨噬细胞IL-1α、IL-1β、TNF-α和IL-6基因的表达[54]。青藤根中的青藤碱成分则有效抑制巨噬细胞分泌TNF-α和IL-1β, 目前都用于治疗RA等自身免疫疾病[55]。
3 总结与展望RA发病机制复杂, 目前还没有较好的治疗药物。传统DMARDs如甲氨蝶呤等起效慢且不良反应大, 生物制剂和小分子抑制剂靶点单一, 具有诱发严重感染和肿瘤的风险, 天然药物成分复杂且易发生过敏反应。RA关节滑膜中炎性巨噬细胞增多, 在慢性滑膜炎中发挥至关重要的作用。近年来研究发现, 巨噬细胞异常代谢参与了RA的病理机制和发生发展, 尤其是关节处的SM。因此, 通过靶向RA关节滑膜中巨噬细胞的代谢酶或者中间代谢物(表 1[11, 56-62]), 纠正活化巨噬细胞的异常代谢, 而通过控制代谢调节巨噬细胞功能用来治疗RA等自身免疫病, 只针对激活的代谢活跃细胞, 不会影响基本免疫功能。这也将最大程度地改善疾病症状, 减轻药物不良反应, 为将来研究炎症免疫反应软调节药物(选择性调控机体组织或者细胞的药物)提供新方向[63]。因此, 对巨噬细胞异常代谢的研究有助于全面阐述RA发病机制, 充分了解RA巨噬细胞的代谢途径可为靶向巨噬细胞治疗RA提供新思路。
作者贡献:王越业是综述的主要撰写人, 完成相关文献资料的查阅以及论文初稿的写作; 常艳教授提供文章的思路和整体的规划, 以及对文章内容和格式的修改等, 是本项目的主要负责人; 魏伟教授给予宏观的指导和思路的设计。全体作者都阅读并同意最终的版本。
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