Effects of thioredoxin reductase 1 on ferroptosis and immune function of dendritic cells in septic mice
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摘要:
目的 探讨硫氧还蛋白还原酶1（TXNRD1）对脓毒症小鼠树突状细胞（DC）铁死亡及免疫功能的影响,为改善创面感染等引起的脓毒症免疫抑制提供依据。 方法 该研究为实验研究。取60只6~8周龄雄性C57BL/6J小鼠,对其行盲肠结扎穿孔（CLP）构建脓毒症模型,分别于CLP术后0（即刻）、6、12、24、48、72 h采用随机数字表法选取10只小鼠,采用CD11c阳选磁珠提取小鼠脾脏DC,采用蛋白质印迹法检测细胞中TXNRD1及抗铁死亡蛋白溶质载体家族7成员11（SLC7A11）、谷胱甘肽过氧化物酶4（GPX4）蛋白表达,采用比色法检测细胞中还原型谷胱甘肽含量,采用活细胞成像技术检测细胞脂质过氧化水平,采用流式细胞术检测主要组织相容性复合体Ⅱ类亚型I-A/I-E和白细胞分化抗原CD80、CD86水平。另取100只6~8周龄雄性C57BL/6J小鼠,采用随机数字表法将其分为玉米油+假伤组、玉米油+CLP组、抑制剂+假伤组、抑制剂+CLP组,每组25只。对2个抑制剂组小鼠行TXNRD1抑制剂金诺芬腹腔注射,对2个玉米油组小鼠行玉米油腹腔注射,1 h后对2个CLP组小鼠行CLP术构建脓毒症模型,对2个假伤组小鼠行假手术。从4组小鼠中各取20只,观察其术后7 d内存活情况并计算存活率；术后24 h同前提取4组分别剩余的5只小鼠的脾脏DC并行相应检测。 结果 与CLP术后0 h比较,小鼠CLP术后24 h细胞中TXNRD1、GPX4与SLC7A11蛋白表达及CLP术后48 h细胞中TXNRD1蛋白表达均显著降低（P<0.05）,小鼠CLP术后24、48 h细胞中还原型谷胱甘肽含量均显著降低（P<0.05）。小鼠CLP术后0、6、12 h细胞脂质过氧化水平低,稍低于CLP术后72 h；CLP术后24、48 h细胞脂质过氧化水平显著高于CLP术后0、6、12、72 h。与CLP术后0 h比较,小鼠CLP术后6、12、24、48、72 h细胞中I-A/I-E、CD80水平及CLP术后12、24、48 h细胞中CD86水平均显著升高（P<0.05）。术后24 h,玉米油+CLP组小鼠细胞中TXNRD1、SLC7A11与GPX4蛋白表达均显著低于玉米油+假伤组（P<0.05）,抑制剂+CLP组小鼠细胞中TXNRD1、SLC7A11与GPX4蛋白表达均显著低于玉米油+CLP组、抑制剂+假伤组（P<0.05）。术后24 h,玉米油+CLP组小鼠细胞中还原型谷胱甘肽含量为（239±32）μg/mg,显著低于玉米油+假伤组的（366±59）μg/mg（P<0.05）；抑制剂+CLP组小鼠细胞中还原型谷胱甘肽含量为（134±19）μg/mg,显著低于抑制剂+假伤组的（355±31）μg/mg及玉米油+CLP组（P值均<0.05）。术后24 h,抑制剂+CLP组小鼠细胞脂质过氧化水平显著高于其余3组。术后24 h,玉米油+CLP组小鼠细胞中I-A/I-E、CD80、CD86水平均显著高于玉米油+假伤组（P<0.05）,抑制剂+CLP组小鼠细胞中I-A/I-E、CD80水平均显著高于抑制剂+假伤组（P<0.05）但均显著低于玉米油+CLP组（P<0.05）,抑制剂+假伤组小鼠细胞中CD86水平显著高于玉米油+假伤组（P<0.05）。术后7 d内,抑制剂+CLP组小鼠存活率显著低于抑制剂+假伤组与玉米油+CLP组（χ2值分别为31.19、3.91,P值均<0.05）。 结论 脓毒症小鼠DC中TXNRD1表达降低,细胞铁死亡增强且免疫功能减弱；抑制DC中TXNRD1将加重细胞铁死亡及免疫功能抑制,且与脓毒症预后不良密切相关。 Abstract:Objective To investigate the effects of thioredoxin reductase 1 (TXNRD1) on ferroptosis and immune function of dendritic cells (DCs) in septic mice, and to provide a basis for improving the immunosuppression in sepsis caused by wound infection. Methods This study was an experimental research. Sixty male C57BL/6J mice aged 6-8 weeks were subjected to cecal ligation and puncture (CLP) to establish sepsis models. Ten mice were selected at 0 (immediately), 6, 12, 24, 48, and 72 h after CLP surgery, respectively, according to the random number table method. Mouse splenic DCs were isolated using CD11c-positive magnetic beads. The protein expressions of TXNRD1, and anti-ferroptosis proteins solute carrier family 7 member 11 (SLC7A11), and glutathione peroxidase 4 (GPX4) in the cells were detected by Western blotting, the reduced glutathione (GSH) content in the cells was measured by colorimetric assay, the lipid peroxidation level was assessed via live-cell imaging technology, and the levels of major histocompatibility complex class Ⅱ subtype I-A/I-E and leukocyte differentiation antigens CD80 and CD86 were detected by flow cytometry. Another 100 male C57BL/6J mice aged 6-8 weeks were divided into corn oil+sham injury group, corn oil+CLP group, inhibitor+sham injury group, and inhibitor+CLP group according to the random number table method, with 25 mice in each group. Mice in the two inhibitor groups were intraperitoneally injected with TXNRD1 inhibitor auranofin, while mice in the two corn oil groups were intraperitoneally injected with corn oil. One hour later, mice in the two CLP groups underwent CLP surgery to establish sepsis models, while mice in the two sham injury groups underwent sham surgery. Twenty mice from each group were selected to observe survival within 7 d post-surgery, and the survival rate was calculated. At 24 h post-surgery, mouse splenic DCs from the remaining 5 mice in each group were collected for corresponding assays as above. Results Compared with those at 0 h after CLP surgery, the protein expressions of TXNRD1, GPX4, and SLC7A11 in mouse cells at 24 h after CLP surgery and the protein expression of TXNRD1 in mouse cells at 48 h after CLP surgery were significantly decreased (P<0.05), the GSH content in mouse cells was significantly decreased at 24 and 48 h after CLP surgery (P<0.05). The lipid peroxidation level in mouse cells was low at 0, 6, and 12 h after CLP surgery, slightly lower than that at 72 h after CLP surgery; the lipid peroxidation levels in mouse cells at 24 and 48 h after CLP surgery were significantly higher than those at 0, 6, 12, and 72 h after CLP surgery. Compared with those at 0 h after CLP surgery, the levels of I-A/I-E and CD80 in mouse cells at 6, 12, 24, 48, and 72 h after CLP surgery and the levels of CD86 in mouse cells at 12, 24, and 48 h after CLP surgery were significantly increased (P<0.05). At 24 h post-surgery, the protein expressions of TXNRD1, SLC7A11, and GPX4 in mouse cells in corn oil+CLP group were significantly lower than those in corn oil+sham injury group (P<0.05), while the protein expressions of TXNRD1, SLC7A11, and GPX4 in mouse cells in inhibitor+CLP group were significantly lower than those in corn oil+CLP group and inhibitor+sham injury group (P<0.05). At 24 h post-surgery, the content of GSH in mouse cells in corn oil+CLP group was (239±32) μg/mg, which was significantly lower than (366±59) μg/mg in corn oil +sham injury group (P<0.05); the content of GSH in mouse cells in inhibitor+CLP group was (134±19) μg/mg, which was significantly lower than (355±31) μg/mg in inhibitor+sham injury group and that in corn oil+CLP group (with both P values <0.05). At 24 h post-surgery, the lipid peroxidation level of mouse cells in inhibitor+CLP group was significantly higher than that in the other three groups (P<0.05). At 24 h post-surgery, the levels of I-A/I-E, CD80, and CD86 in mouse cells in corn oil+CLP group were significantly higher than those in corn oil+sham injury group (P<0.05), while the levels of I-A/I-E and CD80 in mouse cells in inhibitor+CLP group were significantly higher than those in inhibitor+sham injury group (P<0.05) but significantly lower than those in corn oil+CLP group (P<0.05); the level of CD86 in mouse cells in inhibitor+sham injury group was significantly higher than that in corn oil+sham injury group (P<0.05). Within 7 d post-surgery, the survival rate of mice in inhibitor+CLP group was significantly lower than that in inhibitor+sham injury group and corn oil+CLP group (with χ2 values of 31.19 and 3.91, respectively, both P values <0.05). Conclusions In septic mice, the expression of TXNRD1 in DCs is reduced, cell ferroptosis is enhanced, and immune function is weakened. The inhibition of TXNRD1 in DCs will exacerbate cell ferroptosis and immune function suppression, and is closely related to the poor prognosis of sepsis. -
Key words:
- Sepsis /
- Immunity /
- Dendritic cells /
- Oxidative stress /
- Ferroptosis /
- Thioredoxin reductase 1
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参考文献
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图 1 采用蛋白质印迹法检测的小鼠CLP术后各时间点脾脏树突状细胞中TXNRD1及SLC7A11与GPX4蛋白表达
注：TXNRD1为硫氧还蛋白还原酶1,SLC7A11为溶质载体家族7成员11,GPX4为谷胱甘肽过氧化物酶4；条带上方1、2、3、4、5、6分别指示盲肠结扎穿孔（CLP）术后0（即刻）、6、12、24、48、72 h
图 2 小鼠CLP术后各时间点脾脏树突状细胞脂质过氧化水平 BODIPY™ 581/591 C11-Hoechst 33342×126。2A、2B、2C、2D、2E、2F.分别为CLP术后0（即刻）、6、12、24、48、72 h,图2A、2B、2C中细胞脂质过氧化水平低且稍低于图2F,图2D、2E中细胞脂质过氧化水平显著高于图2A、2B、2C、2F
注：CLP为盲肠结扎穿孔；未发生过氧化脂质染色为红色,过氧化脂质染色为绿色,细胞核染色为蓝色
图 3 采用蛋白质印迹法检测的4组小鼠术后24 h脾脏树突状细胞中TXNRD1及SLC7A11与GPX4蛋白表达
注：TXNRD1为硫氧还蛋白还原酶1,SLC7A11为溶质载体家族7成员11,GPX4为谷胱甘肽过氧化物酶4；条带上方1、2及3、4分别指示小鼠腹腔注射玉米油1 h后行假手术、盲肠结扎穿孔（CLP）术的玉米油+假伤组、玉米油+CLP组及小鼠腹腔注射金诺芬1 h后行假手术、CLP术的抑制剂+假伤组、抑制剂+CLP组
图 4 4组小鼠术后24 h脾脏树突状细胞脂质过氧化水平 BODIPY™ 581/591 C11-Hoechst 33342×126。4A、4B、4C、4D.分别为玉米油+假伤组、玉米油+CLP组、抑制剂+假伤组、抑制剂+CLP组,图4A、4C中细胞脂质过氧化水平低,图4B中细胞脂质过氧化水平稍高于图4A、4C,图4D中细胞脂质过氧化水平显著高于图4A、4B、4C
注：未发生过氧化脂质染色为红色,过氧化脂质染色为绿色,细胞核染色为蓝色；玉米油+假伤组、玉米油+盲肠结扎穿孔（CLP）组小鼠腹腔注射玉米油1 h后分别行假手术、CLP术,抑制剂+假伤组、抑制剂+CLP组小鼠腹腔注射金诺芬1 h后分别行假手术、CLP术
图 5 4组小鼠术后7 d内存活率（样本数为20）
注：玉米油+假伤组、玉米油+盲肠结扎穿孔（CLP）组小鼠腹腔注射玉米油1 h后分别行假手术、CLP术,抑制剂+假伤组、抑制剂+CLP组小鼠腹腔注射金诺芬1 h后分别行假手术、CLP术；与玉米油+假伤组比较,aP<0.05；与抑制剂+假伤组比较,bP<0.05；与玉米油+CLP组比较,cP<0.05
Table 1. 小鼠CLP术后各时间点脾脏树突状细胞中TXNRD1及SLC7A11与GPX4蛋白表达比较（
CLP术后时间点 样本数 TXNRD1 SLC7A11 GPX4 0 h（即刻） 3 0.983±0.010 0.88±0.09 0.92±0.10 6 h 3 0.913±0.090 0.79±0.09 0.87±0.08 12 h 3 0.840±0.092 0.70±0.08 0.77±0.11 24 h 3 0.615±0.117 0.57±0.06 0.55±0.09 48 h 3 0.660±0.151 0.71±0.14 0.71±0.13 72 h 3 0.839±0.048 0.77±0.12 0.91±0.16 F值 6.66 3.37 4.54 P值 0.004 0.039 0.015 P1值 0.836 0.643 0.959 P2值 0.293 0.142 0.401 P3值 0.002 0.009 0.008 P4值 0.006 0.176 0.145 P5值 0.291 0.484 >0.999 注：CLP为盲肠结扎穿孔,TXNRD1为硫氧还蛋白还原酶1,SLC7A11为溶质载体家族7成员11,GPX4为谷胱甘肽过氧化物酶4；F值、P值为各时间点间各指标总体比较所得；P1值、P2值、P3值、P4值、P5值分别为CLP术后6、12、24、48、72 h与CLP术后0 h各指标比较所得 
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Table 2. 小鼠CLP术后各时间点脾脏树突状细胞中I-A/I-E及CD80与CD86水平比较（
CLP术后时间点 样本数 I-A/I-E CD80 CD86 0 h（即刻） 3 1 509±160 967±39 1 996±205 6 h 3 4 071±155 3 908±96 1 895±64 12 h 3 6 744±455 5 225±235 4 753±357 24 h 3 5 580±464 7 369±141 3 563±219 48 h 3 4 615±282 4 076±84 2 796±268 72 h 3 2 450±70 1 750±100 1 870±251 F值 122.00 475.90 67.94 P值 <0.001 <0.001 <0.001 P1值 <0.001 <0.001 0.979 P2值 <0.001 <0.001 <0.001 P3值 <0.001 <0.001 <0.001 P4值 <0.001 <0.001 0.007 P5值 0.011 <0.001 0.949 注：CLP为盲肠结扎穿孔,I-A/I-E为主要组织相容性复合体Ⅱ类亚型,CD80和CD86为白细胞分化抗原；F值、P值为各时间点间各指标总体比较所得；P1值、P2值、P3值、P4值、P5值分别为CLP术后6、12、24、48、72 h与CLP术后0 h各指标比较所得
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Table 3. 4组小鼠术后24 h脾脏树突状细胞中TXNRD1及SLC7A11与GPX4蛋白表达比较（
组别 样本数 TXNRD1 SLC7A11 GPX4 玉米油+假伤组 3 0.970±0.032 1.06±0.10 1.13±0.09 玉米油+CLP组 3 0.579±0.126 0.60±0.11 0.75±0.03 抑制剂+假伤组 3 0.794±0.178 0.79±0.04 1.06±0.14 抑制剂+CLP组 3 0.269±0.045 0.25±0.12 0.44±0.17 P1值 0.011 0.002 0.018 P2值 0.002 <0.001 <0.001 P3值 0.288 0.035 0.849 P4值 0.038 0.008 0.045 注：玉米油+假伤组、玉米油+CLP组小鼠腹腔注射玉米油1 h后分别行假手术、CLP术,抑制剂+假伤组、抑制剂+CLP组小鼠腹腔注射金诺芬1 h后分别行假手术、CLP术；TXNRD1为硫氧还蛋白还原酶1,SLC7A11为溶质载体家族7成员11,GPX4为谷胱甘肽过氧化物酶4,CLP为盲肠结扎穿孔；TXNRD1、SLC7A11、GPX4是否使用抑制剂的主效应,F值分别为14.22、32.30、8.35,P值分别为0.006、<0.001、0.020；是否进行CLP的主效应,F值分别为50.48、81.55、54.02,P值均<0.001；二者交互作用,F值分别为1.07、0.63、3.05,P值分别为0.330、0.450、0.119；P1值、P2值、P3值、P4值分别为玉米油+CLP组与玉米油+假伤组、抑制剂+CLP组与抑制剂+假伤组、抑制剂+假伤组与玉米油+假伤组、抑制剂+CLP组与玉米油+CLP组各指标比较所得
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Table 4. 4组小鼠术后24 h脾脏树突状细胞中I-A/I-E及CD80与CD86水平比较（
组别 样本数 I-A/I-E CD80 CD86 玉米油+假伤组 3 3 649±270 6 241±385 9 283±3 698 玉米油+CLP组 3 11 927±249 20 103±677 50 258±2 597 抑制剂+假伤组 3 3 463±173 7 287±404 49 051±3 438 抑制剂+CLP组 3 8 561±506 9 810±326 53 972±2 485 P1值 <0.001 <0.001 <0.001 P2值 <0.001 <0.001 0.283 P3值 0.893 0.096 <0.001 P4值 <0.001 <0.001 0.497 注：玉米油+假伤组、玉米油+CLP组小鼠腹腔注射玉米油1 h后分别行假手术、CLP术,抑制剂+假伤组、抑制剂+CLP组小鼠腹腔注射金诺芬1 h后分别行假手术、CLP术；I-A/I-E为主要组织相容性复合体Ⅱ类亚型,CD80和CD86为白细胞分化抗原,CLP为盲肠结扎穿孔；I-A/I-E、CD80、CD86是否使用抑制剂的主效应,F值分别为89.99、293.00、152.90,P值均<0.001；是否进行CLP的主效应,F值分别为1 276.00、920.00、170.20,P值均<0.001；二者交互作用,F值分别为72.10、440.60、102.90,P值均<0.001；P1值、P2值、P3值、P4值分别为玉米油+CLP组与玉米油+假伤组、抑制剂+CLP组与抑制剂+假伤组、抑制剂+假伤组与玉米油+假伤组、抑制剂+CLP组与玉米油+CLP组各指标比较所得
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