[1]邵天祺,李洋,刘锟,等.核旁斑组装转录本1-微RNA-142a-5p轴对尿酸钠诱导的RAW264.7巨噬细胞炎症反应的影响及其机制的实验研究[J].中医正骨,2026,38(06):26-37.
　SHAO Tianqi,LI Yang,LIU Kun,et al.Effects of nuclear paraspeckle assembly transcript 1-microRNA-142a-5p axis on monosodium urate-induced inflammatory responses in RAW264.7 macrophages and its underlying mechanisms: an experimental study[J].The Journal of Traditional Chinese Orthopedics and Traumatology,2026,38(06):26-37.
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核旁斑组装转录本1-微RNA-142a-5p轴对尿酸钠诱导的RAW264.7巨噬细胞炎症反应的影响及其机制的实验研究()

《中医正骨》[ISSN:1001-6015/CN:41-1162/R]

卷:
第38卷
期数:
2026年06期
页码:
26-37
栏目:
基础研究
出版日期:
2026-06-20

文章信息/Info

Title:
Effects of nuclear paraspeckle assembly transcript 1-microRNA-142a-5p axis on monosodium urate-induced inflammatory responses in RAW264.7 macrophages and its underlying mechanisms: an experimental study
作者:
邵天祺1; 李洋2; 刘锟2; 黄程程3; 杨振国2
1.山东中医药大学第一临床医学院,山东 济南 250014; 2.山东中医药大学第二附属医院,山东 济南 250001; 3.山东中医药大学附属医院,山东 济南 250014
Author(s):
SHAO Tianqi1; LI Yang2; LIU Kun2; HUANG Chengcheng3; YANG Zhenguo2
1.The First Clinical Medical College of Shandong University of Traditional Chinese Medicine,Jinan 250014,Shandong,China; 2.The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine,Jinan 250001,Shandong,China; 3.The Affiliated Hospital of Shandong University of Traditional Chinese Medicine,Jinan 250014,Shandong,China
关键词:
关节炎; 痛风性;  RNA; 长链非编码;  微RNAs;  RAW264.7细胞;  炎症;  模型; 生物学;  实验研究
Keywords:
arthritis; gouty;  RNA; long noncoding;  microRNAs;  RAW 264.7 cells;  inflammation;  models; biological;  experimental study
摘要:
目的:探讨核旁斑组装转录本1(nuclear paraspeckle assembly transcript 1,NEAT1)-微RNA(microRNA,miRNA)-142a-5p轴对尿酸钠诱导的RAW264.7巨噬细胞炎症反应的影响及其机制。方法:①尿酸钠诱导RAW264.7巨噬细胞炎症反应的浓度与时间筛选。将RAW264.7巨噬细胞分为空白对照组和10 μg·mL-1、20 μg·mL-1、40 μg·mL-1、80 μg·mL-1、120 μg·mL-1尿酸钠组。除空白对照组外,其余各组细胞分别加入终浓度为10、20、40、80、120 μg·mL-1的尿酸钠溶液进行干预。检测各组RAW264.7巨噬细胞活力和肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)含量,筛选尿酸钠溶液的最佳干预浓度。再用最佳浓度尿酸钠溶液分别干预RAW264.7巨噬细胞12、24、48 h。检测各时间点RAW264.7巨噬细胞中NEAT1和miRNA-142a-5p的相对表达水平,筛选尿酸钠溶液的最佳干预时间。②抑制NEAT1表达对RAW264.7巨噬细胞炎症反应影响的检测。将RAW264.7巨噬细胞分为空白对照组、模型组、NEAT1抑制阴性对照组和NEAT1抑制组。除空白对照组外,其余3组均加入80 μg·mL-1尿酸钠溶液,孵育24 h。然后NEAT1抑制阴性对照组和NEAT1抑制组分别转染非靶向干扰小RNA和靶向NEAT1的干扰小RNA。检测各组细胞NEAT1和miRNA-142a-5p的相对表达水平、细胞活力、细胞凋亡率,以及细胞中白细胞介素(interleukin,IL)-6、IL-1β、TNF-α含量和IL-1β、IL-6、TNF-α、核苷酸结合结构域富含亮氨酸重复序列和含热蛋白结构域受体3(nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3,NLRP3)、半胱氨酸天冬氨酸蛋白酶-1(cysteine aspartic acid specific protease,caspase-1)、磷酸化核因子κB(phosphorylated nuclear factor κB,p-NF-κB)、核因子κB(nuclear factor κB,NF-κB)的蛋白表达水平; 以p-NF-κB蛋白相对表达量与NF-κB蛋白相对表达量的比值计算NF-κB磷酸化水平。③抑制miRNA-142a-5p表达对沉默NEAT1的RAW264.7巨噬细胞炎症反应影响的检测。将RAW264.7巨噬细胞分为空白对照组、模型组、NEAT1抑制阴性对照组、NEAT1抑制组、NEAT1抑制联合miRNA抑制阴性对照组和NEAT1抑制联合miRNA-142a-5p抑制组。前4组干预方法同实验②,后2组在NEAT1抑制组干预方法的基础上分别转染miRNA抑制剂阴性对照物和miRNA-142a-5p抑制剂。检测各组细胞miRNA-142a-5p的相对表达水平、细胞活力,以及细胞中IL-6、IL-1β、TNF-α的含量和IL-1β、IL-6、TNF-α、NLRP3、caspase-1、p-NF-κB、NF-κB的蛋白表达水平,计算NF-κB磷酸化水平。④NETA1与miRNA-142a-5p靶向结合关系的验证。将巨噬细胞分为NEAT1野生型miRNA抑制阴性对照组、NEAT1野生型miRNA-142a-5p抑制组、NEAT1突变型miRNA抑制阴性对照组和NEAT1突变型miRNA-142a-5p抑制组。NEAT1野生型miRNA抑制阴性对照组和NEAT1野生型miRNA-142a-5p抑制组转染NEAT1野生型报告载体,并分别转染miRNA抑制剂阴性对照物和miRNA-142a-5p抑制剂; 其余2组转染NEAT1突变型报告载体,并分别转染miRNA抑制剂阴性对照物和miRNA-142a-5p抑制剂。采用双萤光素酶报告基因检测系统测定各组萤光素酶荧光值,计算各组相对萤光素酶活性。结果:①尿酸钠诱导RAW264.7巨噬细胞炎症反应的浓度与时间筛选结果。120 μg·mL-1尿酸钠组RAW264.7巨噬细胞的细胞活力低于其他各组(P=0.000,P=0.000,P=0.000,P=0.000,P=0.000); 其他5组之间两两比较,组间差异均无统计学意义。80 μg·mL-1尿酸钠组RAW264.7巨噬细胞中的TNF-α含量高于其他各组(P=0.000,P=0.000,P=0.000,P=0.000,P=0.000)。80 μg·mL-1尿酸钠溶液干预24 h时,RAW264.7巨噬细胞中NEAT1的相对表达水平最高,miRNA-142a-5p的相对表达水平最低。最终筛选出尿酸钠诱导RAW264.7巨噬细胞炎症反应的最佳干预浓度为80 μg·mL-1、最佳干预时间为24 h。②抑制NEAT1表达对RAW264.7巨噬细胞炎症反应影响的检测结果。NEAT1抑制组RAW264.7巨噬细胞中NEAT1的相对表达水平低于模型组和NEAT1抑制阴性对照组(P=0.003,P=0.006),miRNA-142a-5p的相对表达水平高于模型组和NEAT1抑制阴性对照组(P=0.000,P=0.001)。NEAT1抑制组RAW264.7巨噬细胞的细胞活力低于空白对照组(P=0.020),高于模型组和NEAT1抑制阴性对照组(P=0.000,P=0.000); 细胞凋亡率高于空白对照组(P=0.000),低于模型组和NEAT1抑制阴性对照组(P=0.000,P=0.000)。NEAT1抑制组RAW264.7巨噬细胞中IL-1β、IL-6、TNF-α的含量均高于空白对照组(P=0.020,P=0.010,P=0.000),低于模型组和NEAT1抑制阴性对照组(P=0.011,P=0.019,P=0.015; P=0.016,P=0.004,P=0.002); IL-1β、IL-6、TNF-α、NLRP3、caspase-1的蛋白相对表达量均高于空白对照组(P=0.000,P=0.000,P=0.000,P=0.000,P=0.000),低于模型组和NEAT1抑制阴性对照组(P=0.035,P=0.011,P=0.000,P=0.000,P=0.001; P=0.000,P=0.001,P=0.033,P=0.004,P=0.017); NF-κB磷酸化水平高于空白对照组(P=0.000),低于模型组和NEAT1抑制阴性对照组(P=0.003,P=0.013)。③抑制miRNA-142a-5p表达对沉默NEAT1的RAW264.7巨噬细胞炎症反应影响的检测结果。NEAT1抑制联合miRNA-142a-5p抑制组RAW264.7巨噬细胞的细胞活力与细胞中miRNA-142a-5p的相对表达水平均低于NEAT1抑制组和NEAT1抑制联合miRNA抑制阴性对照组(P=0.000,P=0.000; P=0.001,P=0.000); 细胞中IL-1β、IL-6、TNF-α的含量均高于NEAT1抑制组和NEAT1抑制联合miRNA抑制阴性对照组(P=0.013,P=0.032,P=0.004; P=0.006,P=0.001,P=0.002),低于模型组(P=0.036,P=0.006,P=0.013); 与NEAT1抑制阴性对照组相比,该组RAW264.7巨噬细胞中的IL-6含量低(P=0.020)。NEAT1抑制联合miRNA-142a-5p抑制组RAW264.7巨噬细胞中IL-1β、IL-6、TNF-α、NLRP3、caspase-1的蛋白相对表达量均高于NEAT1抑制组和NEAT1抑制联合miRNA抑制阴性对照组(P=0.001,P=0.000,P=0.008,P=0.001,P=0.000; P=0.005,P=0.000,P=0.000,P=0.000,P=0.046),低于模型组和NEAT1抑制阴性对照组(P=0.001,P=0.006,P=0.000,P=0.003,P=0.000; P=0.000,P=0.000,P=0.000,P=0.000,P=0.000); NF-κB磷酸化水平高于NEAT1抑制组和NEAT1抑制联合miRNA抑制阴性对照组(P=0.020,P=0.038),低于模型组和NEAT1抑制阴性对照组(P=0.000,P=0.000)。④NEAT1与miRNA-142a-5p靶向结合关系验证结果。NEAT1野生型miRNA-142a-5p抑制组相对萤光素酶活性高于NEAT1野生型miRNA抑制阴性对照组(P=0.025)。NEAT1突变型miRNA-142a-5p抑制组与NEAT1突变型miRNA抑制阴性对照组的相对萤光素酶活性比较,差异无统计学意义(P=0.486); NEAT1野生型miRNA抑制阴性对照组与NEAT1突变型miRNA抑制阴性对照组的相对萤光素酶活性比较,差异无统计学意义(P=0.780)。结论:NEAT1可介导RAW264.7巨噬细胞炎症反应,参与RAW264.7巨噬细胞的炎症损伤过程,与miRNA-142a-5p有靶向结合关系; 抑制NEAT1的表达能够促进miRNA-142a-5p的表达,进而抑制炎症相关蛋白的表达; NEAT1-miRNA-142a-5p轴对尿酸钠诱导的RAW264.7巨噬细胞炎症反应具有调控作用。
Abstract:
Objective:To investigate the effects of nuclear paraspeckle assembly transcript 1(NEAT1)-microRNA(miRNA)-142a-5p axis on the inflammatory responses of RAW264.7 macrophages induced by monosodium urate(MSU),and to explore its underlying mechanisms.Methods:①Screening the concentration and intervention time of MSU for inducing inflammatory responses in RAW264.7 macrophages.The RAW264.7 macrophages in the logarithmic growth phase were collected and divided into a blank control group and 10,20,40,80,and 120 μg/mL MSU groups.All RAW264.7 macrophages but the ones in the blank control group were stimulated with MSU solutions at final concentrations of 10,20,40,80,and 120 μg/mL,respectively,for 24 hours.Following the end of stimulation,the RAW264.7 macrophages viability and tumor necrosis factor-α(TNF-α)level were measured in each group to identify the optimal intervention concentration of MSU.Subsequently,the RAW264.7 macrophages were treated with MSU solution at the determined optimal concentration for 12,24,and 48 hours,respectively.Following the end of intervention,the relative expression levels of NEAT1 and miRNA-142a-5p in RAW264.7 macrophages at each time point were quantified to identify the optimal intervention time of MSU.②Detecting the effects of NEAT1 knockdown on inflammatory responses in RAW264.7 macrophages.The RAW264.7 macrophages in the logarithmic growth phase were assigned into a blank control group,a model group,a NEAT1 knockdown negative control(NC)group,and a NEAT1 knockdown group.All RAW264.7 macrophages,except those in the blank control group,were treated with the 80 μg/mL MSU solution and incubated for 24 hours.After the end of MSU treatment,the RAW264.7 macrophages in the NEAT1 knockdown NC group and NEAT1 knockdown group were transfected with non-targeting small interfering RNA(siRNA)and NEAT1-targeting siRNA,respectively.Following the successful transfection,the relative expression levels of NEAT1 and miRNA-142a-5p,cell viability,and cell apoptosis rate were measured in each group.Additionally,the levels of interleukin(IL)-6,IL-1β,and TNF-α,as well as the protein expression levels of IL-1β,IL-6,TNF-α,nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor 3(NLRP3),cysteine aspartic acid specific protease(caspase-1),phosphorylated nuclear factor κB(p-NF-κB),and nuclear factor κB(NF-κB),in the RAW264.7 macrophages were detected.The phosphorylation level of NF-κB was calculated using the ratio of the relative protein expression level of p-NF-κB to that of NF-κB.③Detecting the effects of mi-RNA-142a-5p inhibition on the inflammatory responses in NEAT1-silenced RAW264.7 macrophages.The RAW264.7 macrophages in the logarithmic growth phase were divided into a blank control group,a model group,a NEAT1 silencing NC group,a NEAT1 silencing group,a NEAT1 silencing combined with miRNA inhibitor NC group,and a NEAT1 silencing combined with miRNA-142a-5p inhibitor group.The first four groups received the same interventions as those in experiment ②,whereas the last two groups,following the same treatment as the NEAT1 knockdown group,were further transfected with the miRNA inhibitor NC and the miRNA-142a-5p inhibitor,respectively.After the successful transfection,the relative expression levels of miRNA-142a-5p and cell viability were measured in each group.The levels of IL-6,IL-1β,and TNF-α,as well as the protein expression levels of IL-1β,IL-6,TNF-α,NLRP3,caspase-1,p-NF-κB,and NF-κB were determined,and the phosphorylation level of NF-κB was calculated.④Validating the targeted binding interaction between NEAT1 and miRNA-142a-5p.The RAW264.7 macrophages were divided into NEAT1 wild-type miRNA inhibitor NC group,NEAT1 wild-type miRNA-142a-5p inhibitor group,NEAT1 mutant-type miRNA inhibitor NC group,and the NEAT1 mutant-type miRNA-142a-5p inhibitor group.The NEAT1 wild-type miRNA inhibitor NC group and the NEAT1 wild-type miRNA-142a-5p inhibitor group were transfected with the NEAT1 wild-type reporter vectors,along with the miRNA inhibitor NC and the miRNA-142a-5p inhibitor,respectively.The remaining two groups were transfected with the NEAT1 mutant-type reporter vectors, along with the miRNA inhibitor NC and the miRNA-142a-5p inhibitor,respectively.The luciferase activities were measured in each group using a dual-luciferase reporter assay system,and the relative luciferase activities were calculated.Results:①The optimal concentration and treatment time for MSU-induced inflammatory responses in RAW264.7 macrophages.The RAW264.7 macrophages exhibited the lowest cell viability in the 120 μg/mL MSU group(P=0.000,P=0.000,P=0.000,P=0.000,P=0.000).Pairwise comparisons among the other five groups showed no statistically significant differences.The TNF-α level in the RAW264.7 macrophages was the highest in the 80 μg/mL MSU group(P=0.000,P=0.000,P=0.000,P=0.000,P=0.000).Following a 24-hour intervention with 80 μg/mL MSU solution,the relative expression level of NEAT1 in the RAW264.7 macrophages was the highest,while that of miRNA-142a-5p was the lowest.The optimal concentration and intervention time of MSU for inducing the inflammatory responses in RAW264.7 macrophages were ultimately identified as 80 μg/mL and 24 hours,respectively.②Effects of NEAT1 knockdown on the inflammatory responses in RAW264.7 macrophages.The relative expression level of NEAT1 in the RAW264.7 macrophages was lower,whereas that of miRNA-142a-5p was higher in the NEAT1 knockdown group compared to the model group and the NEAT1 knockdown NC group(P=0.003,P=0.006; P=0.000,P=0.001).The cell viability of RAW264.7 macrophages in the NEAT1 knockdown group was lower than that in the blank control group(P=0.020),but higher than those in the model group and the NEAT1 knockdown NC group(P=0.000,P=0.000); however,the cell apoptosis rate of RAW264.7 macrophages in the NEAT1 knockdown group was higher than that in the blank control group(P=0.000),but lower than those in the model group and the NEAT1 knockdown NC group(P=0.000,P=0.000).In addition,in the NEAT1 knockdown group,the levels of IL-1β,IL-6,and TNF-α in the RAW264.7 macrophages were higher than those in the blank control group(P=0.020,P=0.010,P=0.000),but lower than those in the model group and the NEAT1 knockdown NC group(P=0.011,P=0.019,P=0.015; P=0.016,P=0.004,P=0.002); consistently,the relative protein expression levels of IL-1β,IL-6,TNF-α,NLRP3,and caspase-1 were upregulated compared to the blank control group(P=0.000,P=0.000,P=0.000,P=0.000,P=0.000),but downregulated compared to the model group and the NEAT1 knockdown NC group(P=0.035,P=0.011,P=0.000,P=0.000,P=0.001; P=0.000,P=0.001,P=0.033,P=0.004,P=0.017); moreover,the phosphorylation level of NF-κB was higher than that in the blank control group(P=0.000),but lower than those in the model group and the NEAT1 inhibition NC group(P=0.003,P=0.013).③Effects of miRNA-142a-5p inhibition on the inflammatory responses in NEAT1-silenced RAW264.7 macrophages.In the NEAT1-silenced RAW264.7 macrophages,the cell viability and the relative expression level of miRNA-142a-5p in the NEAT1 silencing combined with miRNA-142a-5p inhibitor group were lower than those in the NEAT1 silencing group and the NEAT1 silencing combined with miRNA inhibitor NC group(P=0.000,P=0.000; P=0.001,P=0.000).The levels of IL-1β,IL-6,and TNF-α in the NEAT1 silencing combined with miRNA-142a-5p inhibitor group were higher than those in the NEAT1 silencing group and the NEAT1 silencing combined with miRNA inhibitor NC group(P=0.013,P=0.032,P=0.004; P=0.006,P=0.001,P=0.002),but lower than those in the model group(P=0.036,P=0.006,P=0.013); further compared to the NEAT1 silencing NC group,the IL-6 level was lower in RAW264.7 macrophages of this group(P=0.020).Moreover,the relative protein expression levels of IL-1β,IL-6,TNF-α,NLRP3,and caspase-1 in the NEAT1 silencing combined with miRNA-142a-5p inhibitor group were higher than those in the NEAT1 silencing group and the NEAT1 silencing combined with miRNA inhibitor NC group(P=0.001,P=0.000,P=0.008,P=0.001,P=0.000; P=0.005,P=0.000,P=0.000,P=0.000,P=0.046),but lower than those in the model group and the NEAT1 silencing NC group(P=0.001,P=0.006,P=0.000,P=0.003,P=0.000; P=0.000,P=0.000,P=0.000,P=0.000,P=0.000); and the phosphorylation level of NF-κB was higher than those in the NEAT1 silencing group and the NEAT1 silencing combined with miRNA inhibitor NC group(P=0.020,P=0.038),but lower than those in the model group and the NEAT1 silencing NC group(P=0.000,P=0.000).④Targeted binding interaction between NEAT1 and miRNA-142a-5p.The relative luciferase activity in the NEAT1 wild-type miRNA-142a-5p inhibitor group was significantly higher than that in the NEAT1 wild-type miRNA inhibitor NC group(P=0.025),while no statistically significant difference was observed between the NEAT1 mutant-type miRNA-142a-5p inhibitor group and the NEAT1 mutant-type miRNA inhibitor NC group(P=0.486),nor between the NEAT1 wild-type miRNA inhibitor NC group and the NEAT1 mutant-type miRNA inhibitor NC group(P=0.780).Conclusion:NEAT1,which directly targets miRNA-142a-5p,can mediate the inflammatory responses and involve in the inflammatory injury process in RAW264.7 macrophages.Silencing NEAT1 can up-regulate the expression of miRNA-142a-5p,thereby inhibiting the expression of inflammation-related proteins.These findings indicate that the NEAT1-miRNA-142a-5p axis can modulate the MSU-triggered inflammatory responses in RAW264.7 macrophages.

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备注/Memo

备注/Memo:
基金项目:山东省医药卫生科技项目(202304071638); 山东省中医药科技项目(M-2023143); 山东中医药大学第二附属医院青年科研创新团队项目(院发〔2024〕147号)
通信作者:杨振国 E-mail:yangzhenguo81@163.com
(收稿日期:2026-04-14 本文编辑:杨雅)
更新日期/Last Update: 2026-06-20