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刘追, 陈家乐, 周寅, 等. PD-L1在坏死性小肠结肠炎小鼠模型中的表达和作用[J]. koko体育app 学报(医学版), 2022, 53(3): 414-420. DOI:
引用本文: 刘追, 陈家乐, 周寅, 等. PD-L1在坏死性小肠结肠炎小鼠模型中的表达和作用[J]. koko体育app 学报(医学版), 2022, 53(3): 414-420. DOI:
LIU Zhui, CHEN Jia-le, ZHOU Yin, et al. Expression and Role of PD-L1 in a Mouse Model of Necrotizing Enterocolitis[J]. Journal of Sichuan University (Medical Sciences), 2022, 53(3): 414-420. DOI:
Citation: LIU Zhui, CHEN Jia-le𒊎, ZHOU Yin, et al. Expression and Role of PD-L1 in a Mouse Model of Necღrotizing Enterocolitis[J]. Journal of Sichuan University (Medical Sciences), 2022, 53(3): 414-420. DOI:

PD-L1在坏死性小肠结肠炎小鼠模型中的表达和作用

Expression and Role of PD-L1 in a Mouse Model of Necrotizing Enterocolitis

  • 摘要:
      目的  探讨程序性死亡配体-1(programmed death ligand-1, PD-L1)在坏死性小肠结肠炎(necrotizing enterocolitis, NEC)小鼠模型中的表达和作用。
      方法  采用野生型C57BL/6J小鼠20只,随机分入对照组与造模组,对照组母乳喂养,造模组采用脂多糖+配方奶喂养+缺氧+冷刺激的方法进行NEC诱导,随后取小鼠肠道进行HE染色评估病理改变、免疫荧光共定位检测PD-L1表达定位、Western blot检测肠道PD-L1表达量,并取外周血进行流式分析检测白细胞亚群及其PD-L1表达;取PD-L1(+/+)与PD-L1(−/−)小鼠各14只,随机分入各自基因型对照组与造模组,诱导方法同前,取小鼠肠道进行HE染色评估病理改变,取外周血检测炎症因子表达。
      结果  成功构建NEC小鼠模型,PD-L1在小鼠肠道中表达于肠上皮细胞及炎症细胞,在外周血中表达于T细胞、单核细胞、中性粒细胞;NEC小鼠肠道PD-L1表达较对照组增加,NEC小鼠外周血中T细胞、单核细胞比例及其PD-L1表达较对照组无明显变化,中性粒细胞比例及其PD-L1表达较对照组分别增加约140%和150%(P<0.05);PD-L1基因小鼠实验结果显示,对照组PD-L1(+/+)小鼠与PD-L1(−/−)小鼠肠道情况及血清炎症因子水平无明显差异;PD-L1(−/−)NEC小鼠较PD-L1(+/+)NEC小鼠肠道病理改变加重,平均病理评分增加(P<0.05),同时PD-L1(−/−)NEC小鼠较PD-L1(+/+)NEC小鼠血清白细胞介素(interleukin, IL)-10下降约44%、趋化因子配体1/IL-6/IL-1β均有25%以上的上升(P均<0.05)。
      结论  PD-L1在小鼠中广泛表达于炎症细胞和肠上皮细胞,敲除PD-L1加重了NEC小鼠的炎症反应与肠道病变程度,PD-L1在NEC发病中发挥减轻炎症反应的保护作用,其机制可能与调控中性粒细胞/肠上皮细胞有关。
     
    Abstract:
      Objective  To investigate the expression and role of programmed death ligand-1 (PD-L1) in a mouse model of necrotizing enterocolitis (NEC).
      Methods  A total of 20 wild-type C57BL/6J mice were randomly assigned to the control and the model groups. Mice in the control group were breastfed, while mice in the model group were given lipopolysaccharide, formula feeding, hypoxia, and cold stimulation for NEC induction. Then, the intestines of the mice were collected in order to assess the pathological changes through HE staining, to examine PD-L1 expression and localization with immunofluorescence co-localization, and to evaluate intestinal PD-L1 expression with Western blot. Peripheral blood was collected for flow cytometry to examine leukocyte subpopulations and their PD-L1 expression. On the other hand, 14 PD-L1 (+/+) mice and 14 PD-L1 (−/−) mice were randomly divided into their respective genotype control groups and model groups. The same induction method as was already mentioned was adopted for the model groups. The intestines of the mice were collected for HE staining to evaluate the pathological change and peripheral blood was collected to examine the expression of inflammatory factors.
      Results  The NEC mouse model was successfully constructed. PD-L1 was widely expressed in enterocytes and inflammatory cells in the mouse intestines and in T cells, monocytes, and neutrophils in peripheral blood. The expression of PD-L1 in NEC mouse intestines increased in comparison with that of the control group. In the peripheral blood of NEC mice, the proportion of T cells and monocytes and their PD-L1 expression showed no significant changes compared with those of the control group, while the proportion of neutrophils and their PD-L1 expression increased by about 140% and 150%, respectively, in comparison with those of the control group (P<0.05). According to the results of the PD-L1 gene mouse experiment, the control groups of PD-L1 (+/+) mice and PD-L1 (−/−) mice showed no significant difference in their intestinal conditions and serum inflammatory factor levels, while the PD-L1 (−/−) NEC mouse had worse intestinal pathological changes and increased mean pathological scores compared with those of PD-L1 (+/+) NEC mouse (P<0.05). In addition, serum interleukin (IL)-10 in PD-L1 (−/−) NEC mouse decreased by about 44% compared with that of PD-L1 (+/+) NEC mice, and chemokine (C-X-C motif) ligand 1/IL-6/IL-1β all increased by more than 25% (all P<0.05).
      Conclusion  PD-L1 is widely expressed in inflammatory cells and enterocytes in mice. Knocking out PD-L1 aggravates the degree of NEC inflammation and intestinal pathological changes. PD-L1 plays a protective role by reducing inflammation in the pathogenesis of NEC, the mechanism of which may be related to the regulation of neutrophils/enterocytes.
     
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