炎症因子在帕金森病中的致病机制

发布于 15 小时前  5 次阅读


摘要 帕金森病(PD)是全球第二大神经退行性疾病,该病病情复杂,病程较长,治疗难度较大,对患者家庭和社会带来沉重负担,且目前尚无法治愈。临床运用较多的一线治疗PD的药物只能一定程度上延缓疾病进展,暂时提高患者生活质量。每年在全球仍有许多新发PD病例。关于PD的致病机制众说纷纭,但未完全阐明。最近的研究表明,炎症反应在PD的发生和进展过程中起十分关键的作用。在这篇综述中,作者将简要介绍炎症因子在PD中的致病机制和调节途径,为新一代PD药物开发带来启示。

关键词 帕金森病;炎症因子;免疫介导的器官功能异常;自身免疫

The pathogenic mechanism of inflammatory factors in Parkinson's disease

Abstract Parkinson’s disease is the second largest neurodegenerative disease around the world. Complexity of the disease condition, longer course, more difficult to treat, bring a heavy burden to society and the patients’ family. And it is currently incurable. The first-line drugs commonly used in clinical practice for treating PD can only delay the progression of the disease to a certain extent and temporarily improve the quality of life of patients. Every year, there are still many new cases of PD worldwide. There are various opinions on the pathogenic mechanism of PD, but it has not been fully elucidated. Recent studies have shown that inflammatory response plays a important role in the occurrence and progression of PD. In this review, I will briefly introduce the pathogenic mechanism and regulatory pathways of inflammatory factors in PD, providing insights for the development of new generation PD drugs.

Key words PD; inflammatory factors; immune mediated organ dysfunction; autoimmunity

PD是继阿尔兹海默症(AD)后老年人群中第二常见的神经退行性疾病,影响全球超过1000 万人1,预计 2040 年病例数将超过 1200 万人2。随着中国人均预期寿命的增加和老龄化进程的推进,PD应当越来越受到被的重视。

PD的致病可能与异常α-突触核蛋白(α-Syn)的聚集、线粒体功能障碍、溶酶体或囊泡运输障碍和神经炎症等复杂因素的相互作用有关3,并共同导致是大脑黑质(SN)处多巴胺(DA)能神经元加速死亡4。PD主要表现为震颤、强直、运动迟缓、运动障碍等运动症状和嗅觉减退、色觉受损、幻觉、焦虑、抑郁、早期认知功能障碍、痴呆、快速眼动睡眠行为障碍(RBD)等非运动症状5,6,部分非运动症状可能作为PD前驱症状比运动症状更早出现6

在中枢神经系统(CNS)中,神经元、神经胶质细胞和细胞外微环境的持续相互作用是维持神经元稳态的关键,其紊乱会导致PD等神经退行性疾病。近年来,炎症过程在DA神经元死亡中的作用已成为人们关注的焦点7

炎症因子是由免疫原或其他因子刺激免疫细胞和其他细胞所产生并分泌的低分子量可溶性蛋白,在调控机体免疫的过程中起重要作用。然而,近年来的研究发现,炎症因子不仅是免疫系统调节剂,还是神经系统调节剂。另一方面,炎症因子的产生和平衡也受外周神经系统(PNS)和CNS的调节8。既往研究表明,PD患者的脑脊液(CSF)和黑质纹状体DA区的炎症因子含量显著提高9,在PD患者的SN中发现表达IFN-γ、TNF和IL-1的胶质细胞密度更高10,11。在2023年之前的51项有关PD的临床研究中,有7种标志物(CRP、IL-1β、IL-2、IL-6、IL-8、IFN-γ、TNF-α)被超过5项研究报道12,说明它们的水平变动与PD的关系更大,从而更具有研究价值。

一、炎症因子在PD中的作用

如前文所述,与PD相关的炎症因子很多,下面重点介绍2个与PD关系较大的促炎因子。

2.1 TNF-α

TNF-α是一种17kDa的肽且一般以多聚体的形式存在,其受体在CNS的神经元和神经胶质细胞上表达13。在脑内,TNF-α可由星形胶质细胞、小胶质细胞和某些神经元表达14,15,16

目前已鉴定的的TNF-α受体有两种——TNF-R1和TNF-R217,18,19。由这两种受体介导的途径多种多样,包括G蛋白介导的蛋白激酶A途径、磷脂酶C和磷脂酶A2的激活、一氧化氮和神经酰胺的产生、自由基的形成等。TNFR可以通过半胱天冬酶(caspase)介导细胞凋亡20。Plata-Salaman首先证明了CNS中TNF-α在脑组织中有生物活性和免疫反应性23。TNF-α在PD中通过这一途径诱导了多巴胺能神经元的凋亡21

许多研究表明TNF-α水平与PD存在关系。PD患者脑脊液和死后脑中TNF-α水平升高24。一项针对142位PD患者的临床研究显示,晚期PD患者中外周血中的TNF-α水平高于1期和2期的PD患者,且PD患者的严重程度与其主要由TNF-α介导的中枢神经系统外的炎症程度呈正相关25。TNF-α的水平也与PD患者的非运动症状的严重程度相关。在PD伴抑郁症的患者中,外周血更高水平的TNF-α与更严重的认知困难、抑郁症、焦虑症和睡眠障碍有关22,26,27。然而,也有研究显示,与对照相比,PD患者的TNF-α水平显著降低28,29

TNF-α在CNS中既有神经毒性也有保护性22,但本文中主要讨论其神经毒性的作用。

Angelova和Brown发现了一种基于铁超载的体外建立衰老小胶质细胞表型模型的方法。他们观察到这些小胶质细胞分泌TNF-α增加,这可能影响α-syn的功能,增加其表达和聚集水平30。由于TNF-α过转录激活对蛋白表达的影响通常通过NF-κB通路介导,而在SNCA上确实存在NF-κB的结合位点31,所以这可能是TNF-α影响α-syn的机制。

TNF-α的致病离不开中枢内免疫细胞的作用。一些证据表明炎症因子是血脑屏障(BBB)通透性改变的罪魁祸首,这些证据来自于在体外BBB模型中观察到的各种细胞因子(包括TNFα、IL-1β或IFN-γ)降低跨内皮电阻32。此外,与野生型同窝出生小鼠相比,Tnfa敲除小鼠中MPTP诱导的BBB渗漏减少33

一种反应性星形胶质细胞在CNS损伤和疾病中被强烈诱导,它是反应性星形胶质细胞亚型,我们称之为A1星形胶质细胞,这类细胞具有神经毒性。活化的小胶质细胞通过分泌IL-1α、TNF和C1q来诱导A1星形胶质细胞34。TNF-α可以调节星形胶质细胞、少突胶质细胞和神经元表面MHC分子的表达,进而将自身细胞抗原呈递给淋巴细胞35

在PD病程中会出现谷氨酸代谢障碍引起的谷氨酸诱导的兴奋性毒性,这种病理变化主要由小胶质细胞介导,而TNF-α被视作在其中发挥重要功能的分子36。研究表明,反应性小胶质细胞释放的TNF-α与其受体TNFR1结合,增强了突触处Ca2+渗透性α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体(AMPAR)的运输37。此外,在大鼠海马体切片中,TNF-α可通过NF-κB活化抑制谷氨酸再摄取,进一步促进谷氨酸毒性38。在脑组织内存在谷氨酸-半胱氨酸转运系统(xCs),在PD中,已经证明xCs释放过量的细胞外谷氨酸39。炎症分子如TNF和脂多糖可诱导小胶质细胞表达xCs。从而使小胶质细胞能够释放谷氨酸,传播兴奋性毒性36

2.2 IL-1β

在 PD 的 MPTP 模型中,啮齿动物大脑中的 IL-1β 和 IL-1R1 有所增加40。大量临床研究表明,IL-1β水平在PD患者的血清和CSF中上升或变化没有统计学意义12,39。在感染负担(IB)较高的PD患者中,IL-1β也显著较高41。用快速眼动睡眠行为障碍筛查问卷(RBDSQ)对PD患者进行评估并分组,发现快速眼动睡眠行为障碍组(PRBD)与无快速眼动睡眠行为障碍组(NPRBD)组和对照组相比,PRBD组CSF和血清中IL-1β水平提高42。不同的动物实验表明,脑内高水平IL-1β与脑内DA神经元丧失有关43。事实上,同样作为炎症因子,IL-1β在PD伴其他非运动症状患者中的水平变化与TNF-α其实是类似的26

IL-1β在PD中的致病与核苷酸结合寡聚结构域样蛋白3 (NLRP3)炎症小体介导的细胞焦亡有关44。炎症小体由作为传感器的模式识别受体(PRR)、接头蛋白ASC和作为下游效应分子的半胱天冬酶1前体(pro-caspase-1)组成45,核苷酸结合寡聚化结构域样受体(NLR)或AIM2样受体(ALR)通常充当传感器分子46。NLR识别不同的刺激之后可通过ASC形成多聚体以将pro-caspase-1转化为活性状态47,活化的caspase-1可以切割pro-IL-1β/18使之转化为具有生物活性的炎症因子促进炎症发生,caspase-1本身也具有促进细胞焦亡的作用,细胞焦亡之后又可以释放IL-1β/18使炎症反应扩大48。然而,低浓度的NLRP3炎症小体无法产生效应,所以其浓度先要被事先上调。典型的例子就是脂多糖(LPS)与Toll样受体4(TLR4)结合,通过 NF-κB信号传导增加 NLRP3 的细胞表达49

如上所述,NLRP3炎症小体的激活需要一定的刺激物。在PD中,α-syn可以同时作为TLR和NLRP3炎症小体的激活物诱导小胶质细胞焦亡和IL-1β的释放,从而损伤多巴胺(DA)能神经元50。动物实验表明,对肝脏NLRP3炎症小体的抑制减弱了炎症细胞因子向大脑的传播,并延缓了神经炎症和DA神经元变性的进展,说明NLRP3激活引起的外周炎症也会对大脑DA神经元产生影响51

IL-1β可与其受体IL-1R1结合,募集共受IL-1受体辅助蛋白(IL-1RAcP)并形成三聚体。通过称为Toll和IL-1R样(TIR)结构域的保守胞质区域,三聚体复合物快速组装两种细胞内信号蛋白:骨髓分化初级反应基因88 (MYD88) 和白细胞介素1受体激活蛋白激酶4(IRAK4),然后激活NF-κB通路并诱导炎症因子前体的产生52

IL-1β在PD发病机制中的作用可能不仅仅限于DA神经元损失,利用慢病毒方法在成年雄性SD大鼠的背侧海马中诱导IL-1β的长期过表达,发现大鼠的认知功能受到影响53

IL-1β 还涉及介导家族性 PD 基因的毒性,包括 LRRK2PINK1Parkin54

在PD中可能存在促炎性Th17细胞和抗炎性Treg细胞之间的不平衡,Th17细胞在PD患者的血液中增加,并受到促炎细胞因子IL-1β和IL-6的促进55

白细胞介素-1受体拮抗剂(IL-1RA)在结构上与IL-1α和IL-1β相似,所以可以与IL-1β竞争性结合IL-1R1,但无法和IL-1β一样招募IL-1RAcP形成三聚体启动胞内信号传导56,通过这种方式,IL-1RA作为抗炎细胞因子来调节IL-1β介导的的促炎作用。

目前关于PD中IL-1RA的表达水平的变化了解仍然较少,但也已经有少量相关报道。PD患者血清和血浆中 IL-1RA 水平较低,IL-1RA 水平与新诊断PD患者的疲劳临床评估相关,表明IL-1RA水平也可能导致非运动性PD症状54

2.3 其他

除了上述的TNFα、IL-1β之外,还有很多其他炎症因子在PD患者的血清与CSF中均有不同程度的水平变化,如IL-2、IL-6、IL-8、IL-10和IFN-γ在PD患者体内水平升高12,57。也有少数临床研究提到IL-17、IL-27、TGF-β等细胞因子在PD患者体内水平改变,提示这些细胞因子在PD发展过程中可能的作用12。这些炎症因子大多由中枢内的星形胶质细胞、小胶质细胞和T淋巴细胞分泌,这些细胞浸润中枢神经系统,并在黑质中积聚并分泌促炎细胞因子,刺激周围的免疫细胞,并诱导DA神经元死亡。这提示在炎症因子的介导下的PD 与免疫细胞之间复杂的相互作用有密切关系35

这些炎症因子各自可引起不同的下游通路的激活,从而在PD进展中发挥不同作用。如神经元IFNβ/IFNAR的缺乏会导致mtDNA氧化、突变和缺失,导致氧化应激增加和神经元细胞死亡58。IL-4可以在体外抑制被LPS活化的小胶质细胞的一氧化氮释放,增加小胶质细胞胰岛素样生长因子-1(IGF-1)的释放,减轻了LPS诱导的小胶质细胞介导的运动神经元损伤59

二、炎症因子的调控途径

事实上,不同的表达炎症因子的基因都因其在染色体上定位的不同而有其独特的调控途径,但是如果仅从作用结果来区分不同的炎症因子,那么它们便可以简单地被分为促炎因子和抑炎因子两大类,同一类炎症因子之间在PD致病过程中不同程度地体现出协同性而与另一类炎症因子之间体现出不同程度地拮抗性。所以在PD中的某一致病因素便可以调控下游一群有相似作用结果的炎症因子,下面所介绍的就是这种致病因素的调控途径。

3.1 α-Syn

通过质谱联用PCR、免疫组织化学和功能验证研究进行了定量蛋白质组学研究,发现α-Syn诱导了864个基因的表达增加,包括Irg1Ifit1Pyhin,这些基因上调表现为强大的促炎效应60

高阶寡聚α-Syn通过直接与细胞膜上的异二聚体TLR1/2结合来诱导促炎小胶质细胞表型,导致NF-κB的核转位,并以MyD88依赖的方式增加促炎细胞因子TNF-α和IL-1β白细胞的产生61。而对过表达α-Syn的转基因PD模型小鼠给予靶向TLR2的抗体,可以减轻神经元和星形胶质细胞中α-Syn的积累、神经炎症、神经退行性变和行为缺陷62

体外培养的人类星形胶质细胞中的α-Syn积累触发了对T细胞活化至关重要的共刺激分子的表面表达,即人脑内的星形胶质细胞可能作为APC来呈递α-Syn刺激T细胞反应,从而引起CNS炎症发生63

3.2 基因

目前已鉴定出多个与PD高度相关的突变基因,目前研究最热门的包括SNCALrrk2PrknPink1 Gba4

动物实验表明,Lrrk2缺陷减弱了LPS诱导的诱导型一氧化氮合酶、TNF-α、IL-1β和IL-6的mRNA和/或蛋白表达,核转录因子NF-кB转录活性的降低64。而Eliezer Masliah等人通过进一步研究发现,LRRK2有独立于NF-кB途径的其他炎症因子调控通路:LRRK2可以磷酸化活化T细胞核因子 2(NFATc2) 调节由神经元释放的α-Syn所介导的小胶质细胞的炎症反应65

线粒体功能障碍一直被认为是DA神经元丧失的重要起始因素,因为抑制复合物I的毒素会诱导DA能细胞丧失和PD,其中PrknPink1所分别编码的Parkin和Pink1在诱导线粒体自噬方面十分重要,Pink1可以激活正常情况下处于自身抑制状态的Parkin,使之泛素化多种胞质和线粒体外膜蛋白来行使线粒体自噬的功能。通过诱导线粒体自噬去除受损线粒体,可以减少损伤相关分子模式(DAMPs)释放的作用,从而抑制炎症反应。PrknPink1的突变与家族性PD有密切关系66,67Gba也在线粒体自噬中发挥一定作用66

Richard J. Youle等人发现,Prkn-/-Pink1-/-小鼠以及在线粒体DNA(mtDNA)中积累突变的Prkn-/-小鼠中有强烈的炎症表型,Prkn-/-Pink1-/-小鼠耗竭性运动(exhaustive exercise)或小鼠mtDNA累积突变引起的炎症可以通过Sting的敲除而回补68

3.3 cGAS-STING

DNA是重要的损伤相关分子模式(DAMPs),能够通过与(PRR)相互作用来激活先天免疫系统,由环状GMP-AMP合成酶(cGAS)参与组成的cGAS-STING通路是细胞行使该免疫功能的一条重要通路。当cGAS识别到特定的DNA之后,可以与之形成寡聚复合物活化,将ATP和GTP转化为环状GMP-AMP (cGAMP)。随后,cGAMP结合并激活内质网(ER)中的STING。然后,STING易位至高尔基体并招募TANK结合激酶1 (TBK1)磷酸化自身,磷酸化的 STING反过来招募干扰素调节因子3 (IRF3),导致IRF3被TBK1磷酸化。磷酸化后,IRF3 二聚化并易位至细胞核,最终激活 IFN-I的表达。除了 IRF3之外,STING还招募并激活κB抑制因子激酶(IKK),该激酶在两个N末端丝氨酸处磷酸化κB抑制因子α(IκBα),并触发蛋白酶体中泛素依赖性IκBα降解,IκBα的降解导致NF-κB快速且短暂的核转位,从而产生促炎细胞因子和趋化因子69。即cGAS-STING通路通过引起IRF3和NF-κB的核转位来促进炎症的发生。

大脑内的小胶质细胞cGAS-STING 蛋白表达量最高且具有最直接的功能作用69。在PD中,线粒体损伤引起的mtDNA外漏可以刺激cGAS-STING通路的激活69。有实验表明,αSyn预制原纤维(αSyn-PFF)在体外可诱导DNA双链断裂(DSB),激活γH2A.X(一种与DNA修复有关的组蛋白变体)和TBK1。在αSynPFF小鼠模型中,在DA能神经变性发生之前观察到纹状体小胶质细胞内的TBK1激活和DNA损伤70

3.4 肠道菌群

随着对无菌(GF)动物模型的广泛研究,肠道微生物群与先天免疫之间的联系也得到了广泛的认可。肠道微生物群可以和CNS之间通过各种方式相互联系,达到肠脑之间的相互通讯,肠道和中枢神经系统之间的特定联系被称为微生物肠脑(MGB)轴71。正如BBB的完整性与大脑环境的稳定性有关,而肠上皮屏障(IEB)的完整性与肠道菌群的稳态有关,两者也共同维持包括肠道菌群和神经系统在内的MGB轴的稳定。当屏障被破坏时,可能会导致其渗透性增加,从而导致炎症反应和肠道微生物群的变化72。当微生物群被破坏时,会导致血脑屏障通透性和神经炎症的变化73。肠道菌群也可以通过其代谢产物影响PNS继而影响CNS,也可以直接分泌神经递质。对于与炎症反应调节相关的经典通路如炎症小体通路、IFN-I通路、NF-κB通路和PARK7/DJ-1通路都发现有肠道菌群的影响71

最近研究表明,α-Syn有在肠道和中枢神经系统之间远距离双向传输的途径,其中肠道或迷走神经可能发挥重要作用74。近80%的PD患者会出现便秘,因此推测该病的病因始于肠道菌群75。鱼藤酮诱导的慢性PD小鼠模型表现出肠道微生物群失调和胃肠功能受损,其粪便样本中的阿克曼菌属(Akkermansia)和脱硫弧菌属(Desulfovibrio)细菌的增加。而经过粪便微生物群移植(FMT)治疗的PD小鼠结肠、血清和SN中的LPS水平降低,随后抑制了SN和结肠中的TLR4/MyD88/NF-κB信号通路及其下游促炎产物76

三、总结与展望

免疫系统是生物为了适应环境、保卫自身和清除异己的有力武器,但是随着人们对免疫系统的深入研究,发现免疫系统常常损害自身,正如有观点认为在伤口修复过程中发生的炎症反应实际上不利于“伤口修复”本身77。所以,炎症反应许多人类疾病的致病机制相关,包括本文中提到的PD。由于BBB的存在,人们曾经认为免疫自损不会参与CNS病变,但是越来越多证据指向了相反的方向,关于免疫自损对PD 的致病作用也越来越清晰,相关药物的研发也方兴未艾。目前临床治疗PD常用的一线药物是卡比多巴(Carbidopa)/左旋多巴(Levodopa)或多巴胺激动剂78,而对炎症因子在PD中致病机制和调节机制的深入研究有助于我们发现PD治疗的新靶点,推动新一代的PD药物的开发,从而有望尽可能延缓甚至逆转PD病情。白芍总苷胶囊(TGPC)原是临床中常用于治疗类风湿性关节炎等自身免疫病的药物,研究发现其对MPTP诱导的PD小鼠模型表现出神经保护作用,显著逆转MPTP诱导的PD样行为,抑制小胶质细胞的过度激活。其作用机制可能与调节LRRK2/α-Syn通路有关73。cGAS抑制剂如Compound 102、G-140 (TDI-8077)、G-150 (TDI-8087)等已在体外实验中表现出治疗神经退行性疾病的可能性69。caspase-1抑制剂、阿那白滞素(白介素受体阻滞药)和MCC950(NLRP3抑制剂)的应用都与改善多巴胺能神经元损失和运动缺陷有关1

虽然多种炎症因子在与PD的关系及它们的部分作用机制和调控机制已经得到阐明,但是它们的水平的变化的临床意义尚有争议,它们水平的变化究竟是PD的原因还是结果尚不清楚57。但可以确定的是,炎症与PD的相关性,与神经退行性疾病的相关性,乃至与人类疾病的相关性将依然是研究热点。

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最后更新于 2024-01-05