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中华细胞与干细胞杂志(电子版) ›› 2024, Vol. 14 ›› Issue (02) : 65 -72. doi: 10.3877/cma.j.issn.2095-1221.2024.02.001

论著

miR-9-5p下调CXCR4减轻创伤性脑损伤大鼠的神经炎症和细胞凋亡
王颖1, 吴德平2, 刘煜1, 刘国栋3,†()   
  1. 1. 430012　武汉，中国人民解放军95829部队医院检验病理科
    2. 210002　南京，南京大学医学院附属金陵医院　（东部战区总医院）核医学科
    3. 430012　武汉，中国人民解放军95829部队医院卫勤处
  • 收稿日期:2024-01-15 出版日期:2024-04-01
  • 通信作者: 刘国栋

MiR-9-5p reduces neuroinflammation and apoptosis in rats with traumatic brain injury by down-regulating CXCR4

Ying Wang1, Deping Wu2, Yu Liu1, Guodong Liu3,†()   

  1. 1. Department of Laboratory Pathology, 95829 Army Hospital of the People's Liberation Army of China, Wuhan 430012, China
    2. Department of Nuclear Medicine, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University/General Hospital of Eastern Theater Command, Nanjing 210002, China
    3. Department of Medical Service, 95829 Army Hospital of the People's Liberation Army of China, Wuhan 430012, China
  • Received:2024-01-15 Published:2024-04-01
  • Corresponding author: Guodong Liu
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引用本文：

王颖, 吴德平, 刘煜, 刘国栋. miR-9-5p下调CXCR4减轻创伤性脑损伤大鼠的神经炎症和细胞凋亡[J/OL]. 中华细胞与干细胞杂志(电子版), 2024, 14(02): 65-72.

Ying Wang, Deping Wu, Yu Liu, Guodong Liu. MiR-9-5p reduces neuroinflammation and apoptosis in rats with traumatic brain injury by down-regulating CXCR4[J/OL]. Chinese Journal of Cell and Stem Cell(Electronic Edition), 2024, 14(02): 65-72.

目的

探讨miR-9-5p调控CXC型趋化因子受体4 （CXCR4）减轻创伤性脑损伤（TBI）大鼠的神经炎症和细胞凋亡的机制。

方法

采用液压可控损伤装置制备TBI大鼠模型，随机分为模型组、miR-9-5p agomir组、miR-9-5p阴性对照组、CXCR4激动剂NUCC-390（2.2 mg/ kg）组、miR-9-5p agomir+NUCC-390组，每组12只大鼠，另选12只大鼠设为假手术组。药物分组干预处理后，评测大鼠神经功能缺损评分；Morris水迷宫实验检测大鼠认知能力，比较各组平均逃避潜伏期、穿越平台所在位置次数；TUNEL染色检测大鼠海马神经元凋亡率；试剂盒检测大鼠血清与脑组织中炎性介质白细胞介素-18 （IL-18）、诱导型一氧化氮合酶（iNOS）、肿瘤坏死因子-α （TNF-α）水平；qRT-PCR实验检测大鼠脑组织miR-9-5p、CXCR4 mRNA表达水平；Western blot法检测大鼠脑组织CXCR4及凋亡蛋白Bcl-2、Bcl-2相关X蛋白（Bax）、cleaved caspase-3、caspase-3表达水平。多组间比较采用单因素方差分析，组间两两比较采用SNK-q检验。

结果

与假手术组比较，模型组大鼠穿越平台所在位置次数、脑组织miR-9-5p、Bcl-2表达降低，神经功能缺损评分、平均逃避潜伏期、海马神经元凋亡率[（43.92 ± 4.75）%比（1.31 ± 0.36）%]、血清与脑组织中IL-18、iNOS及TNF-α水平[血清：（156.45 ± 20.62）比（64.59 ± 12.04）ng/L、（67.81 ± 9.56）比（12.03 ± 2.68）U/mL、（78.69 ± 8.56）比（31.52 ± 5.03） ng/ L，脑组织：（169.47 ± 15.61）比（75.58 ± 11.33）ng/g pro、（177.86 ± 19.54）比（82.04 ± 9.67）U/g pro、（151.67 ± 12.57）比（61.58 ± 6.53）ng/g pro]、脑组织CXCR4 mRNA及蛋白表达水平[（1.54 ± 0.32）比（0.97 ± 0.17）、（1.03 ± 0.12）比（0.41 ± 0.10）]、Bax、cleaved caspase-3、caspase-3蛋白表达水平升高（P < 0.05）。与模型组比较，miR-9-5p agomir组大鼠穿越平台所在位置次数、脑组织miR-9-5p、Bcl-2表达均升高，神经功能缺损评分、平均逃避潜伏期、海马神经元凋亡率[（2.10 ± 0.68）%比（43.92 ± 4.75）%]、血清与脑组织中IL-18、iNOS及TNF-α水平[血 清：（68.03 ± 13.15）比（156.45 ± 20.62）ng/L、（14.12 ± 3.71）比（67.81 ± 9.56）U/mL、（33.41 ± 6.40）比（78.69 ± 8.56） ng/ L，脑组织：（82.01 ± 14.16）比（169.47 ± 15.61） ng/ g pro、（91.89 ± 11.72） U/ g pro比（177.86 ± 19.54）U/g pro、（70.01 ± 7.42）比（151.67 ± 12.57） ng/ g pro]、脑组织CXCR4 mRNA及蛋白表达水平[（1.08 ± 0.21）比（1.54 ± 0.32）、（0.45 ± 0.09）比（1.03 ± 0.12）]、脑组织CXCR4 mRNA及蛋白表达水平、Bax、cleaved caspase-3、caspase-3蛋白表达水平均降低（P < 0.05）；NUCC-390可减弱miR-9-5p agomir对TBI大鼠神经功能的改善作用。

结论

miR- 9-5p可通过下调CXCR4表达，减轻神经炎症，抑制海马神经元细胞凋亡，改善TBI大鼠神经功能，增强其认知能力。

关键词: miR-9-5p, CXCR4, 创伤性脑损伤, 神经炎症, 细胞凋亡
Objective

To explore the mechanism of miR-9-5p in reducing neuroinflammation and apoptosis in rats with traumatic brain injury (TBI) by regulating CXC chemokine receptor 4 (CXCR4) .

Methods

The rats with TBI model were constructed by a hydraulic controllable injury device. They were randomly divided into the model group, miR-9-5p agomir group, miR- 9-5p negative control group, CXCR4 agonist NUCC-390 (2.2 mg/kg) group, and miR-9-5p agomir+NUCC-390 group, with 12 rats per group, another 12 rats were selected as the sham group. After intervention with drugs, the neurological deficit scores of rats were evaluated; The Morris water maze experiment was used to test the cognitive ability of rats, and the average escape latency and the times of crossing platform of each group were compared; TUNEL staining was used to detect the apoptosis rate of hippocampal neurons in rats; kits were used to detect the levels of inflammatory mediator interleukin-18 (IL-18) , inducible nitric oxide synthase (iNOS) , and tumor necrosis factor-α (TNF-α) in serum and brain tissue of rats; qRT-PCR experiment was used to detect the expression level of miR-9-5p, CXCR4 mRNA in rat brain tissue; Western blot was used to detect the expression levels of CXCR4, apoptosis protein Bcl- 2, Bcl-2 associated X protein (Bax) , cleaved caspase-3, and caspase-3 in rat brain tissue. One- way analysis of variance was used for comparison among multiple groups, and SNK-q test was used for further pairwise comparison.

Results

Compared with the sham group, the times of crossing platform, brain tissue miR-9-5p, Bcl- 2 expression level of rats in the model group was reduced, the neurological impairment score, average escape latency, hippocampal neuron apoptosis rate [ (43.92 ± 4.75) % vs (1.31 ± 0.36) %], serum and brain tissue IL-18, iNOS and TNF-α levels [serum: (156.45 ± 20.62) vs (64.59 ± 12.04) ng/L, (67.81 ± 9.56) vs (12.03 ± 2.68) U/mL, (78.69 ± 8.56) vs (31.52 ± 5.03) ng/L; brain tissue: (169.47 ± 15.61) vs (75.58 ± 11.33) ng/g pro, (177.86 ± 19.54) vs (82.04 ± 9.67) U/g pro, (151.67 ± 12.57) vs (61.58 ± 6.53) ng/g pro], brain tissue CXCR4 mRNA and protein expression levels [ (1.54 ± 0.32) vs (0.97 ± 0.17) , (1.03 ± 0.12) vs (0.41 ± 0.10) ], Bax, cleaved caspase-3, and caspase-3 protein expression levels were increased (P < 0.05) . Compared with the model group, the times of crossing platform, brain tissue miR-9-5p, Bcl-2 expression level of rats in the miR-9-5p agomir group was increased, the neurological impairment score, average escape latency, hippocampal neuron apoptosis rate [ (2.10 ± 0.68) % vs (43.92 ± 4.75) %], serum and brain tissue IL-18, iNOS and TNF-α levels [serum: (68.03 ± 13.15) vs (156.45 ± 20.62) ng/L, (14.12 ± 3.71) vs (67.81 ± 9.56)  U/ mL, (33.41 ± 6.40) vs (78.69 ± 8.56) ng/L; brain tissue: (82.01 ± 14.16) vs (169.47 ± 15.61) ng/g pro, (91.89 ± 11.72) vs (177.86 ± 19.54) U/g pro, (70.01 ± 7.42) vs (151.67 ± 12.57)  ng/g pro], brain tissue CXCR4 mRNA and protein expression levels [ (1.08 ± 0.21) vs (1.54 ± 0.32, (0.45 ± 0.09) vs (1.03 ± 0.12) ], Bax, cleaved caspase-3, and caspase-3 protein expression levels were decreased (P < 0.05) ; NUCC-390 could attenuate the improving effect of miR-9-5p agomir on nerve function in TBI rats.

Conclusion

MiR-9-5p could down-regulate the expression of CXCR4 to reduce neuroinflammation, inhibit hippocampal neuronal cell apoptosis, improve the nerve function of TBI rats, and enhance their cognitive ability.

Key words: miR-9-5p, CXCR4, Traumatic brain injury, Neuroinflammation, Apoptosis
表1 引物序列信息
基因 序列（5'→3'） 预期扩增长度（bp）
miR-9-5p 上游GCCGCTCTTTGGTTATCTAGCT 189
  下游GTGCAGGGTCCGAGGTAT  
U6 上游CTCGCTTCGGCAGCACA 114
  下游AACGCTTCACGAATTTGCGT  
CXCR4 上游CTCTGAGGCGTTTGGTGCT 325
  下游TGCCCACTATGCCAGTCAAG  
GADPH 上游CTGGAGAAACCTGCCAAGTATG 81
  下游GGTGGAAGAATGGGAGTTGCT  
图1 TUNEL染色观察各组大鼠海马组织神经元凋亡情况（×200，海马CA1区）注：a图为假手术组；b图为模型组；c图为miR-9-5p agomir组；d图为miR-9-5p阴性对照组；e图为NUCC-390组；f图为miR-9-5p agomir+ NUCC-  390组；n为动物数，标尺50 μm
表2 各组大鼠神经功能缺损评分、海马神经元凋亡率、平均逃避潜伏期及穿越平台所在位置次数比较（n = 12， ± s）
分组 神经功能缺损评分（分） 凋亡率（%） 平均逃避潜伏期（s） 穿越平台所在位置次数（次）
假手术组 0.41 ± 0.13 1.31 ± 0.36 9.14 ± 2.35 7.92 ± 1.07
模型组 2.74 ± 0.52a 43.92 ± 4.75a 76.85 ± 10.52a 3.48 ± 0.23a
miR-9-5p阴性对照组 2.83 ± 0.57 43.18 ± 5.61 75.98 ± 11.16 3.46 ± 0.32
miR-9-5p agomir组 0.82 ± 0.27b 2.10 ± 0.68b 11.31 ± 3.08b 7.01 ± 1.85b
NUCC-390组 3.63 ± 0.64b 65.86 ± 7.12b 110.63 ± 15.64b 1.03 ± 0.27b
miR-9-5p agomir+NUCC-390组 2.50 ± 0.71c 42.37 ± 5.12c 75.27 ± 13.01c 3.26 ± 0.85c
F值 71.331 366.683 179.827 87.629
P值 < 0.001 < 0.001 < 0.001 < 0.001
表3 大鼠血清与脑组织炎性介质水平（n = 12， ± s）
分组 血清 脑组织
IL-18 （ng/L） iNOS （U/mL） TNF-α （ng/L） IL-18 （ng/g pro） iNOS （U/g pro） TNF-α （ng/g pro）
假手术组 64.59 ± 12.04 12.03 ± 2.68 31.52 ± 5.03 75.58 ± 11.33 82.04 ± 9.67 61.58 ± 6.53
模型组 156.45 ± 20.62a 67.81 ± 9.56a 78.69 ± 8.56a 169.47 ± 15.61a 177.86 ± 19.54a 151.67 ± 12.57a
miR-9-5p阴性对照组 154.87 ± 23.48 67.04 ± 10.15 80.49 ± 9.82 164.89 ± 20.42 173.84 ± 20.13 62.41 ± 8.84
miR-9-5p agomir组 68.03 ± 13.15b 14.12 ± 3.71b 33.41 ± 6.40b 82.01 ± 14.16b 91.89 ± 11.72b 70.01 ± 7.42b
NUCC-390组 238.56 ± 27.03b 128.56 ± 12.37b 115.78 ± 10.18bc 247.58 ± 26.06b 268.57 ± 26.33bc 243.48 ± 23.85b
miR-9-5p agomir+NUCC-390组 152.42 ± 18.47c 65.12 ± 11.04c 74.93 ± 8.29c 156.48 ± 16.45 169.14 ± 21.01c 140.21 ± 11.94c
F值 129.155 271.358 180.589 150.909 154.506 356.443
P值 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001
图2 Western blot检测各组大鼠脑组织CXCR4及凋亡蛋白表达注：1为假手术组；2为模型组；3为miR-9-5p agomir组；4为miR-9-5p阴性对照组；5为NUCC-390组；6为miR-9-5p agomir+NUCC-390组
表4 大鼠脑组织miR-9-5p、CXCR4 mRNA与蛋白、凋亡蛋白表达水平（n = 12, ± s）
分组 miR-9-5p CXCR4 mRNA CXCR4蛋白 Bax蛋白
假手术组 1.02 ± 0.14 0.97 ± 0.17 0.41 ± 0.10 0.52 ± 0.13
模型组 0.32 ± 0.07a 1.54 ± 0.32a 1.03 ± 0.12a 1.09 ± 0.14a
miR-9-5p阴性对照组 0.31 ± 0.08 1.57 ± 0.29 1.06 ± 0.15 1.07 ± 0.15
miR-9-5p agomir组 0.98 ± 0.13b 1.08 ± 0.21b 0.45 ± 0.09b 0.58 ± 0.12b
NUCC-390组 0.30 ± 0.09b 2.03 ± 0.36b 1.48 ± 0.23b 1.53 ± 0.24b
miR-9-5p agomir+NUCC-390组 0.94 ± 0.13c 1.42 ± 0.34c 0.94 ± 0.11c 1.01 ± 0.17c
F值 133.863 20.707 98.754 62.511
P值 < 0.001 < 0.001 < 0.001 < 0.001
分组 Bcl-2蛋白 caspase-3蛋白 cleaved caspase-3蛋白
假手术组 0.96 ± 0.12 0.70 ± 0.18 0.68 ± 0.14
模型组 0.49 ± 0.05a 1.34 ± 0.20a 1.36 ± 0.21a
miR-9-5p阴性对照组 0.97 ± 0.14 1.37 ± 0.23 1.35 ± 0.20
miR-9-5p agomir组 0.90 ± 0.11b 0.78 ± 0.19b 0.74 ± 0.13b
NUCC-390组 0.11 ± 0.03b 1.93 ± 0.16b 1.91 ± 0.17b
miR-9-5p agomir+NUCC-390组 0.53 ± 0.07c 1.25 ± 0.21c 1.27 ± 0.19c
F值 156.706 62.652 80.463
P值 < 0.001 < 0.001 < 0.001
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