Th17细胞在抑郁发病机制中的作用研究进展
作者：文阅期刊网 来源：文阅编辑中心 日期：2022-09-26 10:07人气：
关键词:辅助性T细胞17;白细胞介素17;抑郁症;脑肠轴;胰岛素抵抗;妊娠期抑郁;
抑郁症是一种常见的精神疾病，其临床表现为持续性的情绪低落、负罪感、自我价值感丧失、睡眠障碍、食欲不佳、疲倦及注意力不集中等，抑郁程度严重时患者可出现自杀倾向。抑郁症可通过缩短端粒长度、加速大脑老化和表观遗传老化来促进生物体衰老，增加罹患其他疾病的风险[1]。抑郁症发病机制尚未明确，主要包括单胺类神经递质数量减少及其受体功能改变、下丘脑-垂体-肾上腺轴(the hypothalamic-pituitary-adrenal axis, HPA axis)紊乱、机体炎症反应、神经可塑性及神经生成障碍、大脑结构改变及功能异常、生存环境及表观遗传改变等[2]。研究[3]表明，抑郁症的发生与免疫激活有关，包括炎症标志物、免疫细胞数量和抗体滴度异常等，不同的抑郁症状与免疫状态变化相关，辅助性T细胞17(T helper cell, Th17 cell)及白细胞介素17(interleukin 17, IL-17)与注意力不集中、自杀倾向、社交障碍、睡眠障碍等抑郁症状有着密切联系[4]。
1 Th17细胞与IL-17
Th17细胞分化过程由转化生长因子-β(transforming growth factor-β, TGF-β)和白细胞介素6 (interleukin 6, IL-6)诱导，并由自身分泌的白细胞介素21(interleukin 21, IL-21)加强，此过程依赖于转录因子维A酸孤核受体γt(retinoid-related orphan receptor-gammat, RORγt)的调控及信号转导转录活化因子3(signal transducer and activator of transcription 3, STAT3)的调节。IL-17A主要由Th17细胞分泌，其他细胞也能产生IL-17A和IL-17F,包括小胶质细胞、星形胶质细胞、神经元、自然杀伤细胞、γδT细胞、中性粒细胞和嗜酸性粒细胞[5]。IL-17家族可以诱导常见的信号通路，包括核转录因子-κB (nuclear factor-kappa B, NF-κB)和线粒体激活蛋白激酶(mitogen-activated protein kinase, MAPK)[MAPK包括p38激酶(p38 mitogen-activated protein kinases, p38 MAPK),c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK)和细胞外信号调节激酶(extracellular signal-regulated kinases, ERK)][6]。
Th17细胞及其分泌的细胞因子在中枢神经系统炎症性疾病的发生发展中具有重要作用，阿尔茨海默病、帕金森病、多发性硬化症、格林-巴利综合征等疾病患者血液中Th17细胞增多，IL-17水平升高[7]。另外，Th17细胞与调节性T细胞(regulatory T cells, Treg细胞)拥有共同的信号通路，均由幼稚CD4+ T细胞分化产生，具有高度可塑性[8],人体内Treg细胞/Th17细胞比值失衡时，可诱发自身免疫性疾病[9]。
2 Th17细胞、IL-17在抑郁发病过程中的作用
一项关于抑郁症患者自杀风险调查[10]显示，患者自杀风险与其体内Th17细胞水平密切相关。临床观察[11]显示，抑郁症患者外周静脉血Th17细胞百分比及Th17细胞/Treg细胞比值相较于健康人升高。研究[12]发现在脑卒中后抑郁症患者血清中IL-17水平升高。习得性无助抑郁小鼠的海马中IL-17水平明显升高[13]。银屑病炎症小鼠模型中，抑郁症状严重程度与IL-17A水平相关，对模型小鼠使用IL-17A抑制剂，可使其抑郁症状缓解，向该实验中野生型小鼠单独使用IL-17A可导致其产生相同的抑郁症状[14];抗抑郁药文拉法辛可通过干预大鼠体内IL-17的表达水平以达到消炎作用[15]。基于加权基因共表达网络，分析抑郁症相关的特定模块和中枢基因，研究中性粒细胞活化过程、T细胞受体信号通路、Th17细胞分化以及这些过程中的中枢基因，有助于阐明抑郁症的发生和进展[16]。Nothdurfter的研究[17]显示IL-17可作为抗抑郁药治疗耐药性的标记，筑波伊弘一郎[18]一项关于社区患有抑郁症妇女血清细胞因子水平变化的研究显示血清IL-17A水平和抑郁症状之间存在密切联系，支持外周IL-17A免疫反应可能是抑郁症的预防和治疗目标这一观点。因此，Th17细胞和IL-17被认为是抑郁症的潜在治疗靶点。
此外，部分研究显示人体长期处于压力状态可引起HPA轴调节功能减弱，皮质醇分泌减少，白细胞转运活化及炎症细胞因子产生受阻，大量Th17细胞向Treg细胞分化，Th17细胞数目相应减少，体内Treg细胞发挥主要抗炎作用[19]。一项慢性轻度不可预知刺激(chronic unpredictable mild stimulation, CUMS)抑郁模型实验中，随着小鼠抑郁症病程发展，其体内Th17细胞数目减少[20]。Grosse等进行的临床观察显示，抑郁症患者随年龄增长，体内Th17细胞成熟受损、数目减少[21]。
2.1 经中枢系统神经免疫介导Th17细胞在抑郁症中的作用
HPA轴反馈机制紊乱、单胺类神经递质减少均可影响抑郁症患者体内Th17细胞数量和IL-17水平。CUMS可激活M1型小胶质细胞，使之分泌促炎介质，导致海马体内IL-17水平上升；CUMS也可破坏HPA轴反馈机制，导致机体糖皮质激素(glucocorticoids, GCs)水平升高，GCs与其位于小胶质细胞上的受体结合，促进小胶质细胞分泌IL-17,增强中枢系统炎症反应[22]。体外细胞培养实验证明5-羟色胺(5-hydroxytryptamine, 5-HT)可抑制Th17细胞分泌IL-17,抑郁症患者大脑内5-HT 减少导致中枢神经系统促炎细胞因子增多[23]。多巴胺(dopamine, DA)主要产生于中枢神经系统，对T细胞具有调节作用，一项多发性硬化症患者外周T细胞培养实验[24]证明，DA可增强Th17细胞表达及其细胞因子的分泌。因此，患者体内单胺类神经递质水平与IL-17水平密切相关。
生理条件下，Th17细胞是调节情绪和海马生长的关键脑营养细胞，对大脑不具有破坏性[25]。病理条件下，由Th17细胞分泌的IL-17A具有中枢毒性[26],可通过激活小鼠中枢神经系统的NF-κB和p38 MAPK炎症信号通路引发抑郁症[27]。小鼠连续3天急性快速动眼睡眠不足会导致IL-17A、IL-17F的分泌增多，并激活海马体内的p38 MAPK通路，抑制齿状回神经细胞生成[28]。Th17细胞进入大脑后，分泌IL-17A及其他促炎因子，引起氧化和亚硝化应激反应，从而对大脑产生直接或间接的影响[29]。IL-17A与位于小胶质细胞上的特异性受体IL-17RA、IL-17RC结合后，激活小胶质细胞释放一氧化氮(nitric oxide, NO)和诱导型一氧化氮合酶(nitric oxide synthase, NOS)并产生神经毒性[30]。据体外实验[31]证明，人类Th17细胞可通过IL-17和IL-22破坏血脑屏障，增加其通透性，促进其他免疫细胞进入中枢神经系统。炎症因素导致存在于小胶质细胞、星形胶质细胞和神经元的吲哚胺2,3-双加氧酶(indoleamine 2, 3-dioxygenase, IDO)过度激活，促进色氨酸转化为具有神经毒性的犬尿氨酸(kynurenine, KYN),从而减少色氨酸向5-HT转化，最终通过降低5-HT水平，影响神经元生成及可塑性导致抑郁症[32]。IL-17基因敲除可促进小鼠海马齿状回的神经元生成增加、突触功能增强，并减少炎性细胞因子表达，从而改善小鼠抑郁症状[33]。
2.2 经脑肠轴介导Th17细胞在抑郁症中的作用
“脑肠轴”是指中枢神经系统与肠道神经系统之间包含多个重叠路径的双向通路，涉及免疫系统、神经系统、肠道微生物及其代谢产物[34]。肠道免疫细胞通过脑肠轴与中枢神经系统产生联系，免疫细胞本身转移或分泌细胞因子通过血液循环系统进入大脑。Th17细胞主要存在于肠道黏膜中，病理状态下进入外周血液循环[35]。研究[36]表明，肠道微生物及其代谢产物在神经炎症机制中发挥重要作用，肠道微生物群的特定成分与促炎细胞因子的产生和Th17细胞的后续生成有关，色氨酸代谢物可通过作用于丙烯酸碳氢化合物受体(acrylic acid hydrocarbon receptor, AHR)和Th17细胞或星形细胞抑制促炎活动。肠道菌群失调、Treg/Th17细胞比例失衡、肠黏膜通透性增加均可导致情绪障碍[37]。
肠道菌群可通过改变海马体区糖皮质激素受体信号通路及炎症信号通路诱导小鼠产生抑郁行为[38]。肠道固有层分布大量Th17细胞，分节丝状菌(segmented filamentous bacteria, SFB)能够调节肠黏膜Th17细胞分化和肠道适应性免疫应答。研究[39]证实，患有抑郁症状的患者粪便与健康人粪便样本对比IL-17A和SFB水平增加。慢性应激小鼠在肠道微生物群及其代谢产物的作用下可导致其IL-17的表达水平上调[40]。向健康小鼠转移抑郁症患者粪便菌群和健康人类的粪便菌群，接受抑郁患者菌群的小鼠相较于接受健康人菌群的小鼠明显表现出抑郁样行为，提示肠道微生物菌群失调可导致小鼠抑郁[41]。Simpson等[42]关于焦虑和抑郁肠道微生物群的meta分析显示，患有抑郁的小鼠及人类肠道中拟杆菌门丰度下降而厚壁菌门增加，同时它们与抑郁行为密切相关。肠道Th17细胞可通过IL-17调节微生物群丰度及宿主代谢，向小鼠移植Th17细胞可导致拟杆菌门显著增加及厚壁菌门的减少，使小鼠肠道微生物群恢复正常[43]。
2.3 经胰岛素抵抗介导在Th17细胞抑郁症中的作用
研究显示，大脑自身可以产生胰岛素[44,45],大脑神经元胰岛素mRNA的表达会随细胞外的葡萄糖浓度升高而增加[46],胰岛素受体在整个大脑的神经元及胶质细胞中广泛表达[47],胰岛素作用于中枢神经系统可调节认知行为和全身代谢[48],胰岛素在神经系统的发育中起着至关重要的作用。脑胰岛素信号受损会增加精神疾病的患病风险[49],胰岛素抵抗可引发认知障碍和抑郁症[50]。IL-17与IL-17R结合可激活NF-κB通路，上调炎症因子基因表达水平，增加促炎细胞因子IL-1β、IL-6、 肿瘤坏死因子α(tumor necrosis factor alpha, TNF-α)水平，诱导胰岛素抵抗的发生[51]。IL-17基因表达促使TNF-α增加[52],由TNF-α激活的JNK和NF-κB信号通路可抑制胰岛素受体底物-1(insulin receptor substrate -1, IRS-1),阻滞胰岛素下游信号传导，形成胰岛素抵抗[53]。一项关于生命早期压力对小鼠葡萄糖代谢影响的研究显示，母婴分离模型小鼠体内IL-17增多，同时胰岛素抵抗较正常小鼠增强[54],提示压力、IL-17、胰岛素抵抗与抑郁的发生存在一定的联系。
2.4 Th17细胞在妊娠期抑郁中的作用
炎症细胞因子在孕妇精神疾病发生发展中起着重要作用，孕妇抑郁程度与Th17细胞及其相关细胞因子(IL-17A、IL-22)存在密切联系[55]。孕妇妊娠期间Th1/Th2平衡与否具有重要意义，妊娠期抑郁患者周围循环中的促炎细胞因子及其可溶性受体和超敏C反应蛋白等增多，Th1/Th2比值失衡并向Th1/Th17转化，这一促炎活动可导致患者体内单胺类神经递质减少、HPA轴紊乱、胎盘免疫功能异常，从而触发或加重妊娠期间的抑郁症状[56]。孕妇长期处于慢性应激状态可能会抑制胎儿神经生成，导致神经元萎缩，进而引起胎儿大脑的病理变化，造成胎儿发育不良。由Th17细胞分泌的IL-17,可穿过胎盘屏障与IL-17受体结合，增强其在胎儿大脑中的信号强度，影响胎儿的大脑发育[57]。
2.5 IL-21、IL-22与抑郁的相关性
Th17细胞分泌的细胞因子还包括IL-21、IL-22,IL-21以自分泌的方式促进淋巴细胞向Th17表型分化，IL-22是 IL-10家族成员之一，其表达只能由IL-6诱导。在各种自身免疫性疾病患者(包括RA、SLE等)的外周血和组织中IL-21水平升高。在Davami等[58]的研究中，抑郁症患者体内IL-21水平相较于健康人差异无统计学意义；Gałecka等[59]的研究显示，抑郁症患者IL-21水平相较于健康人升高。IL-22在自身免疫性疾病中发挥着重要作用[60]。研究[61]显示，使用IL-22抑制剂可调控MAPK的表达从而达到治疗癌症合并抑郁小鼠的效果。Himmerich等[62]的研究显示，压力并不能引起Wistar大鼠体内的IL-22表达水平的变化。IL-21与IL-22与抑郁症的确切联系及在抑郁症发病机制中的具体作用有待于进一步的挖掘。
3 总结与展望
社会环境压力、躯体疾病、心理因素等均可过度激活神经系统免疫导致抑郁症的发生[63,64],Th17细胞及IL-17在中枢神经系统疾病中发挥重要作用，其可通过引发中枢神经系统炎症反应，抑制大脑海马体神经元生成，破坏肠道微生物平衡干预脑肠轴或阻滞胰岛素信号通路产生胰岛素抵抗从而导致抑郁的发生，Th17细胞或可作为抑郁的诊断标记及治疗目标(见图1)。因此，探究Th17细胞及IL-17水平在抑郁发病机制中的作用，结合分子生物学、网络药理学、代谢组学等手段研究抗抑郁药物治疗中Th17细胞及IL-17的相应变化，可为抑郁症的防治提供新的靶点。
参考文献
[1] ALEXOPOULOS G S.Mechanisms and treatment of latelife depression[J].Transl Psychiatry,2019,1:188．
[2] MALHI G S,MANN J J.Depression[J].Lancet,2018,392(10161):2299-2312．
[3] ALVES L P,ROCHA N S.Different cytokine patterns associate with melancholia severity among inpatients with major depressive disorder[J].Ther Adv Psychopharmacol,2020,10:2045125320937921．
[4] BEUREL E,TOUPS M,NEMEROFF C B.The bidirectional relationship of depression and inflammation:double trouble[J].Neuron,2020,107(2):234-256．
[5] MOYNES D M,VANNER S J,LOMAX A E.Participation of interleukin 17A in neuroimmune interactions[J].Brain Behav Immun,2014,41:1-9．
[6] LI X,BECHARA R,ZHAO J,et al.IL-17 receptorbased signaling and implications for disease[J].Nat Immunol,2019,20(12):1594-1602．
[7] 张微，杨萍萍，迟立君．辅助性T细胞17在神经系统变性疾病中的研究进展[J]．医学综述，2017,23(12):2318-2322,2327．
[8] 王柔嘉，常春康．调节性T细胞在骨髓增生异常综合征危险分层中的研究进展[J]．诊断学理论与实践，2021,20(2):221-224．
[9] FIGUEIREDO A S,SCHUMACHER A.The T helper type17/regulatory T cell paradigm in pregnancy[J].Immunology,2016,148(1):13-21．
[10] SCHIWECK C,VALLES-COLOMER M,AROLT V,et al.Depression and suicidality:A link to premature T helper cell aging and increased Th17 cells[J].Brain Behav Immun,2020,87:603-609．
[11] GHOSH R,KUMAR P K,MITRA P,et al.Circulating Thelper 17 and IFN-γpositive Th17 cells in major depressive disorder[J].Behav Brain Res,2020,394:112811．
[12] 张志强，张莉．脑卒中后抑郁患者血清皮质醇、白细胞介素-17、-18的表达[J]．中国老年学杂志，2018,38(17):4125-4127．
[13] CHENG Y,DESSE S,MARTINEZ A,et al.TNFα disrupts blood brain barrier integrity to maintain prolonged depressivelike behavior in mice[J].Brain Behav Immun,2018,69:556-567．
[14] OSBORNE L M,BRAR A,KLEIN S L.The role of Th17 cells in the pathophysiology of pregnancy and perinatal mood and anxiety disorders[J].Brain Behav Immun,2018,76:7-16．
[15] KAMEL K M,GAD A M,MANSOUR S M,et al.Venlafaxine alleviates complete Freund’s adjuvant-induced arthritis in rats:Modulation of STAT-3/IL-17/RANKL axis[J].Life Sci,2019,226:68-76．
[16] ZHANG G,XU S,YUAN Z,et al.Weighted gene coexpression network analysis identifies specific modules and hub genes related to major depression[J].Neuropsychiatr Dis Treat,2020,16:703-713．
[17] NOTHDURFTER C,MILENKOVIC V M,SARUBIN N,et al.The cytokine IL-17A as a marker of treatment resistance in major depressive disorder?[J].Eur J Neurosci,2021,53(1):172-182．
[18] TSUBOI H,SAKAKIBARA H,MINAMIDA Y,et al.Elevated levels of serum IL-17A in community-dwelling women with higher depressive symptoms[J].Behav Sci(Basel),2018,8(11):102．
[19] PUKHALSKY A L,SHMARINA G V,ALIOSHKIN V A,et al.HPA axis exhaustion and regulatory T cell accumulation in patients with a functional somatic syndrome:recent view on the problem of Gulf War veterans[J].J Neuroimmunol,2008,196(1-2):133-138．
[20] HONG M,ZHENG J,DING Z Y,et al.Imbalance between Th17 and Treg cells may play an important role in the development of chronic unpredictable mild stress-induced depression in mice[J].Neuroimmunomodulation,2013,20(1):39-50．
[21] GROSSE L,HOOGENBOEZEM T,AMBRÉE O,et al.Deficiencies of the T and natural killer cell system in major depressive disorder:T regulatory cell defects are associated with inflammatory monocyte activation[J].Brain Behav Immun,2016,54:38-44．
[22] CAI Z A,YPZ A,YYL A,et al.Minocycline ameliorates depressive behaviors and neuro-immune dysfunction induced by chronic unpredictable mild stress in the rat[J].Behav Brain Res,2019,356:348-357．
[23] SACRAMENTO P M,MONTEIRO C,DIAS A,et al.Serotonin decreases the production of Th1/Th17 cytokines and elevates the frequency of regulatory CD4+T cell subsets in multiple sclerosis patients[J].Eur J Immunology,2018,48(8):1376-1388．
[24] FERREIRA T B,BARROS P O,TEIXEIRA B,et al.Dopamine favors expansion of glucocorticoid-resistant IL-17-producing T cells in multiple sclerosis[J].Brain Behav Immun,2014,41:182-190．
[25] BEUREL E,LOWELL J A,JOPE R S.Distinct characteristics of hippocampal pathogenic TH17 cells in a mouse model of depression[J].Brain Behav Immun,2018,73:180-191．
[26] VALLES-COLOMER M,FALONY G,DARZI Y,et al.The neuroactive potential of the human gut microbiota in quality of life and depression[J].Nat Microbiol,2019,4(4):623-632．
[27] NADEEM A,AHMAD S F,AL-HARBI N O,et al.IL-17A causes depression-like symptoms via NFκB and p38MAPK signaling pathways in mice:Implications for psoriasis associated depression[J].Cytokine,2017,97:14-24．
[28] CUI L,XUE R,ZHANG X,et al.Sleep deprivation inhibits proliferation of adult hippocampal neural progenitor cells by a mechanism involving IL-17 and p38 MAPK[J].Brain Res,2019,1714:81-87．
[29] BEUREL E,LOWELL J A.Th17 cells in depression[J].Brain Behav Immun,2018,69:28-34．
[30] CUI M,DAI W,KONG J,et al.Th17 cells in depression:Are they crucial for the antidepressant effect of ketamine?[J].Front Pharmacol,2021,12:649144．
[31] SLYEPCHENKO A,MAES M,KÖHLER C A,et al.Thelper 17 cells may drive neuroprogression in major depressive disorder:Proposal of an integrative model[J].Neurosci Biobehav Rev,2016,64:83-100．
[32] BLINIEWSKA-KOWALSKA K,SZEWCZYK B,GAECKAM,et al.Is interleukin 17 (IL-17) expression a common point in the pathogenesis of depression and obesity?[J].JClin Med,2020,9(12):4018．
[33] LIU Q,XIN W,HE P,et al.Interleukin-17 inhibits adult hippocampal neurogenesis[J].Sci Rep,2014,4:7554．
[34] QUIGLEY,EAMONN M M.Microbiota-brain-gut axis and neurodegenerative diseases[J].Curr Neurol Neurosci Rep,2017,17(12):94．
[35] POWELL N,MACDONALD T T.Recent advances in gut immunology[J].Parasite Immunol,2017,39(6)．
[36] HAASE S,HAGHIKIA A,WILCK N,et al.Impacts of microbiome metabolites on immune regulation and autoimmunity[J].Immunology,2018,154(2):230-238．
[37] 张静，王凯旋，盛放，等．孤独症谱系障碍儿童肠道菌群多样性与Treg-Th17的相关性研究[J]．中华全科医学，2020,18(8):1324-1326,1330．
[38] RAO X,LIU L,WANG H,et al.Regulation of gut microbiota disrupts the glucocorticoid receptor pathway and inflammation-related pathways in the mouse hippocampus[J].Exp Neurobiol,2021,30(1):59-72．
[39] MEDINA-RODRIGUEZ E M,MADORMA D,O’CON-NOR G,et al.Identification of a signaling mechanism by which the microbiome regulates Th17 cell-mediated depressive-like behaviors in mice[J].Am J Psychiatry,2020,177(10):974-990．
[40] VODI C KAA M,ERGANGA P,HRN CÍR B T,et al.Microbiota affects the expression of genes involved in HPA axis regulation and local metabolism of glucocorticoids in chronic psychosocial stress[J].Brain Behav Immun,2018,73:615-624．
[41] ZHENG P,ZENG B,ZHOU C,et al.Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism[J].Mol Psychiatry,2016,21:786-796
[42] SIMPSON C A,ARTECHE C D,ELIBY D,et al.The gut microbiota in anxiety and depression-a systematic review[J].Clin Psychol Rev,2021,83:101943．
[43] HONG C P,PARK A,YANG B G,et al.Gut-specific delivery of T-Helper 17 cells reduces obesity and Insulin resistance in mice[J].Gastroenterology,2017,152(8):1998-2010．
[44] MAZUCANTI C H,LIU Q R,LANG D,et al.Insulin is produced in choroid plexus and its release is regulated by serotonergic signaling[J].JCI Insight,2019,4(23):e131682．
[45] LEE J,KIM K,CHO J H,et al.Insulin synthesized in the paraventricular nucleus of the hypothalamus regulates pituitary growth hormone production[J].JCI Insight,2020,5(16):e135412．
[46] MOLNAR G,FARAGO N,KOCSIS A K,et al.GABAergic neurogliaform cells represent local sources of insulin in the cerebral cortex[J].J Neurosci,2014,34(4):1133-1137．
[47] CAI W,XUE C,SAKAGUCHI M,et al.Insulin regulates astrocyte gliotransmission and modulates behavior[J].JClin Invest,2018,128(7):2914-2926．
[48] KULLMANN S,KLEINRIDDERS A,SMALL D M,et al.Central nervous pathways of insulin action in the control of metabolism and food intake[J].Lancet Diabetes Endocrinol,2020,8(6):524-534．
[49] SOTO M,CAI W,KONISHI M,et al.Insulin signaling in the hippocampus and amygdala regulates metabolism and neurobehavior[J].Proc Natl Acad Sci U S A,2019,116(13):6379-6384．
[50] AGRAWAL R,RENO C M,SHARMA S,et al.Insulin action in the brain regulates both central and peripheral functions[J].Am J Physiol Endocrinol Metab,2021,8(6):524-534．
[51] VELIKOVA T V,KABAKCHIEVA P P,ASSYOV Y S,et al.Targeting inflammatory cytokines to improve type 2 diabetes control[J].Biomed Res Int,2021,2021:7297419．
[52] PIROLA L,FERRAZ J C.Role of pro-and anti-inflammatory phenomena in the physiopathology of type 2 diabetes and obesity[J].World J Biol Chem,2017,8(2):120-128．
[53] ZHOU Q,WU X H,WU X M,et al.Vitamin C deficiency aggravates tumor necrosis factor α-induced insulin resistance[J].Eur J Pharmacol,2018,829:1-11．
[54] ILCHMANN-DIOUNOU H,OLIER M,LENCINA C,et al.Early life stress induces type 2 diabetes-like features in ageing mice[J].Brain Behav Immun,2019,80:452-463．
[55] GELMAN P L,MANCILLA-HERRERA I,FLORES-RAMOS M,et al.The cytokine profile of women with severe anxiety and depression during pregnancy[J].BMC Psychiatry,2019,19(1):104．
[56] LEFF-GELMAN P,MANCILLA-HERRERA I,FLORES-RAMOS M,et al.The immune system and the role of inflammation in perinatal depression[J].Neurosci Bull,2016,32(4):398-420．
[57] GAŁECKA M,BLIZ'NIEWSKA-KOWALSKA K,MAESM,et al.Update on the neurodevelopmental theory of depression:is there any’unconscious code’?[J].Pharmacol Rep,2021,73(2):346-356．
[58] DAVAMI M H,BAHARLOU R,VASMEHJANI A A,et al.Elevated IL-17 and TGF-βserum levels:a positive correlation between T-helper 17 cell-related pro-inflammatory responses with major depressive disorder[J].Basic Clin Neurosci,2016,7(2):137-142．
[59] GAŁECKA M,BLIZ'NIEWSKA-KOWALSKA K,ORZECHOWSKA A,et al.Inflammatory versus anti-inflammatory profiles in major depressive disorders-the role of IL-17,IL-21,IL-23,IL-35 and foxp3[J].J Pers Med,2021,11(2):66．
[60] YANG H,HAN L,ZHOU Y J,et al.Lower serum interleukin-22 and interleukin-35 levels are associated with disease status in neuromyelitis optica spectrum disorders[J].CNS Neurosci Ther,2020,26(2):251-259．
[61] ZHANG H J,CHEN M,LIU Y,et al.Paroxetine combined with fluorouracil plays a therapeutic role in mouse models of colorectal cancer with depression through inhibiting IL-22expression to regulate the MAPK signaling pathway[J].Exp Ther Med,2020,20(6):240．
[62] HIMMERICH H,FISCHER J,BAUER K,et al.Stressinduced cytokine changes in rats[J].Eur Cytokine Netw,2013,24(2):97-103．
[63] 丁颖，闫成锐，马晓丽，等．社区空巢老人焦虑抑郁现状及影响因素分析[J]．安徽医学，2019,40(8):947-950．
[64] MAENG S H,HONG H.Inflammation as the potential basis in depression[J].Int Neurourol J,2019,23(Suppl 2):S63-S71.
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