Effects of Krüppel-like factor 4 on inflammatory response and organ injury in septic mice
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摘要:
目的 探讨Krüppel样因子4（KLF4）在巨噬细胞炎症反应中的表达特点与作用及其对脓毒症小鼠炎症反应与脏器损伤的作用，为烧创伤脓毒症的靶向治疗奠定理论基础。 方法 采用实验研究方法。取小鼠RAW264.7巨噬细胞与从10只6~8周龄雄性C57BL/6J小鼠中提取的原代腹腔巨噬细胞（PM）进行实验。采用内毒素/脂多糖（LPS）分别处理RAW264.7巨噬细胞与PM 0（未处理）、1、2、4、6、8、12、24 h构建巨噬细胞炎症反应模型，采用实时荧光定量反转录PCR（RT-PCR）法检测白细胞介素1β（IL-1β）、IL-6、CC趋化因子配体2（CCL2）与肿瘤坏死因子α（TNF-α）mRNA表达，据此确定后续部分实验LPS处理时间。用LPS处理RAW264.7巨噬细胞0、8 h，采用免疫荧光法检测KLF4的定位与蛋白表达；利用高通量测序技术平台对细胞进行转录组测序，采用DESeq2软件筛选2种处理时间细胞间的差异表达基因（DEG）。采用LPS分别处理RAW264.7巨噬细胞与PM 0、1、2、4、6、8、12、24 h，分别用实时荧光定量RT-PCR法与蛋白质印迹法检测KLF4的mRNA与蛋白表达。将RAW264.7巨噬细胞按随机数字表法分为阴性对照组与KLF4过表达组，分别转染对应质粒后用LPS处理0、8 h，采用实时荧光定量RT-PCR法检测KLF4、IL-1β、IL-6、CCL2与TNF-α的mRNA表达，采用蛋白质印迹法检测KLF4蛋白表达。前述实验样本数均为3。将40只6~8周龄雄性C57BL/6J小鼠按随机数字表法分为KLF4过表达组和阴性对照组（每组20只），分别注射相应转染注射液后构建盲肠结扎穿孔脓毒症模型。采用随机数字表法从2组小鼠中各选取12只，观察建模后72 h内生存情况。于建模后8 h取2组分别剩余的8只小鼠，先行眼球取血，采用酶联免疫吸附测定法检测血清中IL-1β、IL-6水平，采用干化学法检测血清中丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）水平；后取心脏、肺脏、肝脏组织，行苏木精-伊红染色后观察损伤情况。对数据行独立样本t检验、Cochran&Cox近似t检验、单因素方差分析、Dunnett检验、Brown-Forsythe和Welch单因素方差分析、Dunnett T3检验、log-rank（Mantel-Cox）检验。 结果 与LPS处理0 h比较，LPS处理6 h与8 h RAW264.7巨噬细胞中IL-1β mRNA表达、LPS处理4~12 h RAW264.7巨噬细胞中IL-6 mRNA表达、LPS处理8 h和12 h RAW264.7巨噬细胞中CCL2 mRNA表达以及LPS处理4~8 h RAW264.7巨噬细胞中TNF-α mRNA表达均显著上调（P<0.05或P<0.01），LPS处理4~8 h PM中IL-1β与CCL2 mRNA表达、LPS处理2~24 h PM中IL-6 mRNA表达以及LPS处理2~12 h PM中TNF-α mRNA表达均显著上调（P<0.05或P<0.01）。选取8 h作为后续部分实验的LPS处理时间。KLF4主要定位在RAW264.7巨噬细胞的细胞核中。与LPS处理0 h比较，LPS处理8 h RAW264.7巨噬细胞中KLF4蛋白表达明显减少；LPS处理8 h RAW264.7巨噬细胞中有1 470个差异表达显著的DEG，包括转录表达显著下调的KLF4［错误发现率<0.05，log2（差异倍数）=-2.47］。与LPS处理0 h比较，LPS处理6~24 h RAW264.7巨噬细胞中KLF4 mRNA表达、LPS处理1~24 h RAW264.7巨噬细胞与PM中KLF4蛋白表达以及LPS处理4~24 h PM中KLF4的mRNA表达均明显降低（P<0.05或P<0.01）。与阴性对照组比较，KLF4过表达组LPS处理0、8 h RAW264.7巨噬细胞中KLF4的mRNA（t'值分别为17.03、8.61，P<0.05或P<0.01）与蛋白表达均明显升高，LPS处理0 h RAW264.7巨噬细胞中IL-6、CCL2的mRNA表达均明显升高（t值分别为6.29、3.40，P<0.05或P<0.01），LPS处理8 h RAW264.7巨噬细胞中IL-1β、IL-6、CCL2、TNF-α的mRNA表达均显著下降（t值分别为10.52、9.60、4.58、8.58，P<0.01）。KLF4过表达组小鼠建模后72 h内生存比例明显高于阴性对照组（χ2=4.01，P<0.05）。建模后8 h，KLF4过表达组小鼠血清中IL-1β、IL-6与ALT、AST水平分别为（161±63）、（476±161）pg/mL与（144±24）、（264±93）U/L，明显低于阴性对照组的（257±58）、（654±129）pg/mL与（196±27）、（407±84）U/L（t值分别为3.16、2.44与4.04、3.24，P<0.05或P<0.01）。建模后8 h，与阴性对照组比较，KLF4过表达组小鼠心脏、肺脏、肝脏的组织结构紊乱减轻，炎性渗出明显减少，脏器实质细胞病理样改变明显减轻。 结论 KLF4在LPS诱导的巨噬细胞炎症反应中表达显著下降，显著抑制巨噬细胞炎症反应；KLF4显著提高脓毒症小鼠生存率并缓解炎症反应与脓毒症相关脏器损伤。 Abstract:Objective To explore the expression characteristics and role of Krüppel-like factor 4 (KLF4) in macrophage inflammatory response and its effects on inflammatory response and organ injury in septic mice, so as to lay a theoretical foundation for targeted treatment of burns and trauma sepsis. Methods The method of experimental research was used. Mouse RAW264.7 macrophages and primary peritoneal macrophages (PMs) isolated from 10 male C57BL/6J mice aged 6-8 weeks were used for the experiments. RAW264.7 macrophages and PMs were treated with endotoxin/lipopolysaccharide (LPS) for 0 (without treatment), 1, 2, 4, 6, 8, 12, and 24 h, respectively, to establish macrophage inflammatory response model. The mRNA expression of interleukin 1β (IL-1β), IL-6, CC chemokine ligand 2 (CCL2) and tumor necrosis factor-α (TNF-α) were detected by real-time fluorescence quantitative reverse transcription polymerase chain reaction (RT-PCR), and the LPS treatment time was determined for some of the subsequent experiments. RAW264.7 macrophages were treated with LPS for 0 and 8 h, the localization and protein expression of KLF4 were detected by immunofluorescence method, transcriptome sequencing of the cells was performed using the high-throughput sequencing technology platform, and the differently expressed genes (DEGs) between the two time points treated cells were screened by DESeq2 software. RAW264.7 macrophages and PMs were treated with LPS for 0, 1, 2, 4, 6, 8, 12, and 24 h, respectively, and the mRNA and protein expressions of KLF4 were detected by real-time fluorescence quantitative RT-PCR and Western blotting, respectively. RAW264.7 macrophages were divided into negative control (NC) group and KLF4-overexpression group according to the random number table, which were treated with LPS for 0 and 8 h respectively after transfection of corresponding plasmid. The mRNA expressions of KLF4, IL-1β, IL-6, CCL2, and TNF-α were detected by real-time fluorescence quantitative RT-PCR, while the protein expression of KLF4 was detected by Western blotting. The number of samples in aforementioned experiments was all 3. Forty male C57BL/6J mice aged 6-8 weeks were divided into KLF4-overexpression group and NC group (with 20 mice in each group) according to the random number table, and the sepsis model of cecal ligation perforation was established after the corresponding transfection injection was injected respectively. Twelve mice were selected from each of the two groups according to the random number table, and the survival status within 72 hours after modeling was observed. Eight hours after modeling, the remaining 8 mice in each of the two groups were selected, the eyeball blood samples were collected to detect the levels of IL-1β and IL-6 in serum by enzyme-linked immunosorbent assay, and the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum by dry chemical method. Subsequently, the heart, lung, and liver tissue was collected, and the injury was observed after hematoxylin-eosin staining. Data were statistically analyzed with independent sample t test, Cochran & Cox approximate t test, one-way analysis of variance, Dunnett test, Brown-Forsythe and Welch one-way analysis of variance, Dunnett T3 test, log-rank (Mantel-Cox) test. Results Compared with that of LPS treatment for 0 h, the mRNA expressions of IL-1β in RAW264.7 macrophages treated with LPS for 6 h and 8 h, the mRNA expressions of IL-6 in RAW264.7 macrophages treated with LPS for 4-12 h, the mRNA expressions of CCL2 in RAW264.7 macrophages treated with LPS for 8 h and 12 h, and the mRNA expressions of TNF-α in RAW264.7 macrophages treated with LPS for 4-8 h were significantly up-regulated (P<0.05 or P<0.01), while the mRNA expressions of IL-1β and CCL2 in PMs treated with LPS for 4-8 h, the mRNA expressions of IL-6 in PMs treated with LPS for 2-24 h, and the mRNA expressions of TNF-α in PMs treated with LPS for 2-12 h were significantly up-regulated (P<0.05 or P<0.01). Eight hours was selected as the LPS treatment time for some of the subsequent experiments. KLF4 mainly located in the nucleus of RAW264.7 macrophages. Compared with those of LPS treatment for 0 h, the protein expression of KLF4 in RAW264.7 macrophages treated with LPS for 8 h was obviously decreased, and there were 1 470 statistically differentially expressed DEGs in RAW264.7 macrophages treated with LPS for 8 h, including KLF4 with significantly down-regulated transcriptional expression (false discovery rate<0.05, log2 (fold change)=-2.47). Compared with those of LPS treatment for 0 h, the mRNA expressions of KLF4 in RAW264.7 macrophages treated with LPS for 6-24 h, the protein expressions of KLF4 in RAW264.7 macrophages and PMs treated with LPS for 1-24 h, and the mRNA expressions of KLF4 in PM treated with LPS for 4-24 h were significantly decreased (P<0.05 or P<0.01). Compared with those in NC group, the mRNA (with t' values of 17.03 and 8.61, respectively, P<0.05 or P<0.01) and protein expressions of KLF4 in RAW264.7 macrophages treated with LPS for 0 h and 8 h in KLF4-overexpression group were significantly increased, the mRNA expressions of IL-6 and CCL2 increased significantly in RAW264.7 macrophages treated with LPS for 0 h (with t values of 6.29 and 3.40, respectively, P<0.05 or P<0.01), while the mRNA expressions of IL-1β, IL-6, CCL2, and TNF-α decreased significantly in RAW264.7 macrophages treated with LPS for 8 h (with t values of 10.52, 9.60, 4.58, and 8.58, respectively, P<0.01). The survival proportion of mice within 72 h after modeling in KLF4-overexpression group was significantly higher than that in NC group (χ2=4.01, P<0.05). Eight hours after modeling, the serum levels of IL-1β, IL-6 and ALT, AST of mice in KLF4-overexpression group were (161±63), (476±161) pg/mL and (144±24), (264±93) U/L, respectively, which were significantly lower than (257±58), (654±129) pg/mL and (196±27), (407±84) U/L (with t values of 3.16, 2.44 and 4.04, 3.24, respectively, P<0.05 or P<0.01) in NC group. Eight hours after modeling, compared with those in NC group, the disorder of tissue structure of heart, lung, and liver, inflammatory exudation, and pathological changes of organ parenchyma cells in KLF4-overexpression group were obviously alleviated. Conclusions The expression of KLF4 is significantly down-regulated in LPS-induced macrophage inflammatory response, which significantly inhibits the macrophage inflammatory response. KLF4 significantly enhances the survival rate of septic mice and alleviates inflammatory response and sepsis-related organ injury. -
Key words:
- Sepsis /
- Macrophages /
- Kruppel-like transcription factors /
- Endotoxins /
- Inflammatory response /
- Organ injury
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参考文献
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1 LPS处理各时间点小鼠RAW264.7巨噬细胞及PM中各炎症因子的mRNA表达（样本数为3，
注：图1A与1C中处理0（未处理）、1、2 h及图1B与1D中处理0 h的均数趋近于横坐标；IL为白细胞介素，CCL2为CC趋化因子配体2，TNF-α为肿瘤坏死因子α，LPS为内毒素/脂多糖，PM为腹腔巨噬细胞；与LPS处理0 h比较，aP<0.01，bP<0.05
2 LPS处理不同时间点小鼠RAW264.7巨噬细胞中KLF4的定位与蛋白表达 Alexa Fluor 594-4',6-二脒基-2-苯基吲哚×20。2A、2B、2C.分别为LPS处理0 h（未处理）细胞核染色、KLF4染色、细胞核与KLF4染色重叠图片，细胞核完整，KLF4蛋白表达较多且主要定位在细胞核中；2D、2E、2F.分别为LPS处理8 h细胞核染色、KLF4染色、细胞核与KLF4染色重叠图片，细胞核完整，图2E中KLF4蛋白表达较图2B减少
注：LPS为内毒素/脂多糖；细胞核阳性染色为蓝色，Krüppel样因子4（KLF4）阳性染色为红色
3 小鼠RAW264.7巨噬细胞经LPS处理8 h相较于LPS处理0 h（未处理）的差异表达基因可视化火山图
注：FDR为错误发现率，KLF4为Krüppel样因子4，LPS为内毒素/脂多糖
4 采用蛋白质印迹法检测LPS处理各时间点小鼠RAW264.7巨噬细胞与腹腔巨噬细胞中KLF4蛋白表达。4A.RAW264.7巨噬细胞；4B.腹腔巨噬细胞
注：KLF4为Krüppel样因子4，GAPDH为3-磷酸甘油醛脱氢酶；条带上方1、2、3、4、5、6、7、8分别指示内毒素/脂多糖（LPS）处理0（未处理）、1、2、4、6、8、12、24 h
5 采用蛋白质印迹法检测LPS处理2个时间点2组小鼠RAW264.7巨噬细胞中KLF4蛋白表达
注：KLF4为Krüppel样因子4，GAPDH为3-磷酸甘油醛脱氢酶；条带上方1、3分别指示内毒素/脂多糖（LPS）处理0（未处理）、8 h阴性对照组，2、4分别指示LPS处理0、8 h KLF4过表达组
7 2组脓毒症小鼠建模后8 h脏器损伤情况 苏木精-伊红×200。7A、7B、7C.分别为阴性对照组肝脏、肺脏、心脏组织，肝细胞存在空泡样变性且部分肝小叶正常结构破坏，肺间质与肺泡腔内可见大量粉红色炎性渗出，心肌细胞排列紊乱且间质水肿；7D、7E、7F.分别为Krüppel样因子4过表达组肝脏、肺脏、心脏组织，肝细胞形态较图7A正常且肝小叶结构完整，肺泡腔内渗出较图7B明显减少且肺间质无明显异常，心肌组织损伤较图7C轻且心肌细胞排列较整齐
表1 采用实时荧光定量反转录PCR法检测小鼠RAW264.7巨噬细胞与腹腔巨噬细胞炎症因子mRNA表达的引物序列及产物大小
基因名称 引物序列（5'→3'） 产物大小（bp） 白细胞介素1β 上游：GAAATGCCACCTTTTGACAGTG 116 下游：TGGATGCTCTCATCAGGACAG 白细胞介素6 上游：CTGCAAGAGACTTCCATCCAG 131 下游：AGTGGTATAGACAGGTCTGTTGG 肿瘤坏死因子α 上游：CAGGCGGTGCCTATGTCTC 89 下游：CGATCACCCCGAAGTTCAGTAG CC趋化因子配体2 上游：TAAAAACCTGGATCGGAACCAAA 120 下游：GCATTAGCTTCAGATTTACGGGT 3-磷酸甘油醛脱氢酶 上游：AGGTCGGTGTGAACGGATTTG 95 下游：GGGGTCGTTGATGGCAACA 
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表2 2组小鼠RAW264.7巨噬细胞经LPS处理各时间点KLF4与炎症因子mRNA表达比较（
组别与时间点 样本数 KLF4 IL-1β IL-6 CCL2 TNF-α 阴性对照组 0 h 3 1.00±0.09 1.00±0.11 1.0±0.5 1.00±0.19 1.00±0.08 8 h 3 0.21±0.04 2 099.00±260.50 5 115.0±706.5 2 575.00±375.50 155.40±20.73 KLF4过表达组 0 h 3 150.10±26.27 1.32±0.23 3.9±0.6 2.13±0.54 1.24±0.61 8 h 3 113.30±22.74 435.10±84.53 1 085.0±172.5 1 342.00±276.10 41.42±10.02 统计量值1 t'=17.03 t=2.16 t=6.29 t=3.40 t=0.67 P1值 0.003 0.097 0.003 0.027 0.846 统计量值2 t'=8.61 t=10.52 t=9.60 t=4.58 t=8.58 P2值 0.013 0.001 0.001 0.009 0.001 注：LPS为内毒素/脂多糖，KLF4为Krüppel样因子4，IL为白细胞介素，CCL2为CC趋化因子配体2，TNF-α为肿瘤坏死因子α，统计量值1、P1值，统计量值2、P2值分别为LPS处理0（未处理）、8 h时2组间比较所得
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表3 2组脓毒症小鼠建模后8 h血清中炎症因子与脏器功能指标水平（
组别 样本数 IL-1β（pg/mL） IL-6（pg/mL） ALT（U/L） AST（U/L） 阴性对照组 8 257±58 654±129 196±27 407±84 KLF4过表达组 8 161±63 476±161 144±24 264±93 t值 3.16 2.44 4.04 3.24 P值 0.007 0.028 0.001 0.006 注：KLF4为Krüppel样因子4，IL为白细胞介素，ALT为丙氨酸转氨酶，AST为天冬氨酸转氨酶
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