有氧运动通过TLR4/miR-223/NLRP3信号通路轴介导CUMS抑郁小鼠海马炎症反应
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摘要
目的:探讨有氧运动激活慢性不可预见性应激(CUMS)抑郁小鼠海马TLR4/miR-223/NLRP3信号通路改善海马功能的作用。方法:8周龄雄性C57BL/6小鼠60只,随机数字法分为空白对照组(CG)、抑郁模型组(MG)、模型运动组(ME)、TLR4抑制剂组(TG)和TLR4抑制剂+运动组(TE),每组12只。除空白对照组外的其他小鼠均进行为期28天的慢性应激性抑郁造模。造模后进行神经行为学评定,造模成功的ME、TE组小鼠适应性运动1周后进行为期8周的中等强度跑台运动,抑制剂组进行为期4周的TAK-242腹腔注射。训练8周后当日评定各组小鼠的神经行为学改变,次日取样,ELISA法测定血清IL-1β和IL-10含量,尼氏染色检测海马尼氏体形态,海马组织进行m RNA和miRNA的高通量测序及关联分析,免疫组化法测定TLR4、IL-1β、IL-10和NF-κB蛋白阳性表达区域面积,RT-PCR检测海马NLRP3、TLR4、IL-1β、IL-10、NF-κB和mi R-223的表达,WesternBlot检测海马TLR4、IL-10和IL-1β蛋白定性表达。结果:CUMS抑郁小鼠神经行为学功能显著下降,血液IL-1β含量明显增多,海马尼氏体核固缩严重。8周的有氧运动能够有效改善CUMS抑郁小鼠海马功能,降低血清IL-1β含量,显著减少海马组织尼氏体核固缩,降低小鼠的绝望行为,增加求生欲望。miRNA与m RNA高通量测序及关联分析结果显示,mi R-223与NLRP3存在靶向调控作用,且受运动干预的影响。ME组小鼠NLRP3、TLR4、IL-1β、NF-κB等炎症相关因子的表达下调,抗炎因子IL-10表达增强,miR-223表达增强。抑郁小鼠TLR4被抑制后,下游转录子NF-κB表达降低,mi R-223表达增强,NLRP3蛋白表达降低,炎性作用下降。TE组小鼠也观察到一致的抗炎症效果。结论:有氧运动可显著降低CUMS抑郁小鼠海马TLR4表达,激活TLR4/miR-223/NLRP3通路轴,改善抑郁小鼠海马功能,拮抗抑郁小鼠海马组织炎症,促进损伤的海马组织修复。
Objective: The purpose of this study was to explore the effects of aerobic training on the hippocampal inflammation by activating the hippocampal TLR4/miR-223/NLRP3 signal pathway in mice with chronic unpredictable mild stress depression(CUMS). Methods: Sixty 8-week-old male C57 BL/6 mice were divided into control group(CG), CUMS model group(MG), CUMS model plus exercise group(ME), TLR4 inhibitor group(TG) and TLR4 inhibitor plus exercise group(TE)(n =12).Except CG, the CUMS was molded in mice of the other four groups by suffering from chronic stress for 28 days. Both ME group and TE group were trained for 8 weeks by running on a treadmill in moderate-intensity. TG group and TE group were received intraperitoneal injection of TAK-242, which was an inhibitor of TLR4, for 4 weeks. The neurobehavioral scores were tested after the 8-week training for all mice. Then, the samples were collected the day after their last training. The level of blood IL-1β and IL-10 were measuredby ELISA kit, the morphology of Nissl body in hippocampus were detected by Nissl staining, the positive expression areasof TLR4, IL-1β, IL-10 and NF-κB protein weredetected by immunohistochemistry, the gene expression levels of hippocampus NLRP3, TLR4, IL-1β, IL-10, NF-κB and miR-223 were examined by RT-PCR, and the protein expression levels of hippocampus TLR4, IL-1β and IL-10 were tested by Western Blot. Results: The neurobehavioral function of CUMS mice was significantly decreased, the inflammatory factors such as IL-1β in blood were significantly increased, and the Nissl body nuclear pyknosis were observed. 8-week aerobic training improved the hippocampus function in CUMS micesignificantly, it also reduced the level of IL-1β in blood and Nissl body nuclear pyknosis the desperate behaviorswere reduced and thedesire to survive was increased in the mice. High-throughput sequencing and correlation analysis of miRNA and mRNA showed that there was targeting regulatory relations between miR-223 and NLRP3, which was influencedby exercise intervention. The expressions of inflammatory factors such as NLRP3, TLR4, IL-1β and NF-κBweredecreased and the anti-inflammatory cytokines IL-10 was enhanced in ME mice. The expressions of NF-κB and NLRP3 were down-regulated and the miR-223 was over-expression in TG mice, while the anti-inflammatory effects was increased. The consistent anti-inflammatory effects were also found in TE mice. Conclusion: Aerobic training significantly reduced the expression of TLR4 in the hippocampus of CUMS depression mice, while the TLR4/miR-223/NLRP3 pathway axis was activated, thusthe hippocampus functionwas improved in depressed mice,and the inflammation was reduced and the repair of hippocampal inflammatory injury was enhanced as well.
Objective: The purpose of this study was to explore the effects of aerobic training on the hippocampal inflammation by activating the hippocampal TLR4/miR-223/NLRP3 signal pathway in mice with chronic unpredictable mild stress depression(CUMS). Methods: Sixty 8-week-old male C57 BL/6 mice were divided into control group(CG), CUMS model group(MG), CUMS model plus exercise group(ME), TLR4 inhibitor group(TG) and TLR4 inhibitor plus exercise group(TE)(n =12).Except CG, the CUMS was molded in mice of the other four groups by suffering from chronic stress for 28 days. Both ME group and TE group were trained for 8 weeks by running on a treadmill in moderate-intensity. TG group and TE group were received intraperitoneal injection of TAK-242, which was an inhibitor of TLR4, for 4 weeks. The neurobehavioral scores were tested after the 8-week training for all mice. Then, the samples were collected the day after their last training. The level of blood IL-1β and IL-10 were measuredby ELISA kit, the morphology of Nissl body in hippocampus were detected by Nissl staining, the positive expression areasof TLR4, IL-1β, IL-10 and NF-κB protein weredetected by immunohistochemistry, the gene expression levels of hippocampus NLRP3, TLR4, IL-1β, IL-10, NF-κB and miR-223 were examined by RT-PCR, and the protein expression levels of hippocampus TLR4, IL-1β and IL-10 were tested by Western Blot. Results: The neurobehavioral function of CUMS mice was significantly decreased, the inflammatory factors such as IL-1β in blood were significantly increased, and the Nissl body nuclear pyknosis were observed. 8-week aerobic training improved the hippocampus function in CUMS micesignificantly, it also reduced the level of IL-1β in blood and Nissl body nuclear pyknosis the desperate behaviorswere reduced and thedesire to survive was increased in the mice. High-throughput sequencing and correlation analysis of miRNA and mRNA showed that there was targeting regulatory relations between miR-223 and NLRP3, which was influencedby exercise intervention. The expressions of inflammatory factors such as NLRP3, TLR4, IL-1β and NF-κBweredecreased and the anti-inflammatory cytokines IL-10 was enhanced in ME mice. The expressions of NF-κB and NLRP3 were down-regulated and the miR-223 was over-expression in TG mice, while the anti-inflammatory effects was increased. The consistent anti-inflammatory effects were also found in TE mice. Conclusion: Aerobic training significantly reduced the expression of TLR4 in the hippocampus of CUMS depression mice, while the TLR4/miR-223/NLRP3 pathway axis was activated, thusthe hippocampus functionwas improved in depressed mice,and the inflammation was reduced and the repair of hippocampal inflammatory injury was enhanced as well.
引文
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戈含笑,魏宏文,张有志,等,2017.有氧运动对慢性应激大鼠脑海马区神经可塑性的影响[J].北京体育大学学报,45(5):39-45.
耿元文,林琴琴,马宏敏,等,2018.间歇有氧运动激活心梗大鼠肾脏miR-21/TLR4/NF-κB通路抑制肾脏炎症反应[J].北京体育大学学报,41(1):70-74.
郭音,罗赤苗,陈嘉勤,等,2017.NF-κB信号通路在小鼠阻塞性黄疸及运动与黑果枸杞多糖干预中的差异表达[J].中国体育科技,53(4):119-124,137.
洪灯,齐亚灵,张彦慧,等,2011.简单易操作的大鼠CUMS抑郁模型的构建方法[J].中国卫生产业,8(24):3-4.
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李小龙,2016.有氧运动改善阿尔茨海默病大鼠认知功能损害的综述免疫机制的研究[D].太原:太原理工大学.
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林小晶,鲁林,王晓慧,2017.炎症因子chemerin在有氧运动改善动脉粥样硬化大鼠血脂和主动脉硬化中的作用[J].上海体育学院学报,41(4):49-56.
刘敏,冯连世,王晓慧,2015.4周有氧运动对肥胖青少年胰岛素抵抗及炎症因子的影响[J].上海体育学院学报,39(3):87-89,94.
刘雯,郭文洁,徐强,等,2016.NLRP3炎症小体调控机制研究进展[J].药学学报,51(10):1505-1512.
屈红林,陈惠宇,2008.运动引起应激与应激性疾病的研究进展[J].中国康复医学杂志,23(8):768-770.
屈红林,谢军,陈嘉勤,等,2018.有氧运动激活BDNF/miR-195/Bcl-2信号通路轴抑制CUMS抑郁小鼠海马神经细胞凋亡[J],天津体育学院学报,33(2):148-155.
唐茂婷,吴茜,张慧敏,等,2017.有氧运动在老年痴呆患者中的研究进展[J].中国老年学杂志,37(21):5462-5464.
王卉,刘绍生,夏志,等,2017.长期有氧运动对代谢综合征大鼠炎症及心肌组织过氧化物酶体增殖物激活受体α表达的影响[J].中国康复医学杂志,32(12):1351-1355.
魏永宝,杨金瑞,尹焯,等,2016.miR-223生物学功能及在肿瘤中作用[J].创伤与急诊电子杂志,4(3):166-184、151.
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