抑制PHLPP2通过NLRP3/caspase-1轴减轻细胞因子表达改善小鼠抑郁样行为进展

孔思瑾; 王立金; 万娟; 焦东亮

doi:10.13898/j.cnki.issn.2097-5252.2025.01.013

抑制PHLPP2通过NLRP3/caspase-1轴减轻细胞因子表达改善小鼠抑郁样行为进展

Inhibition of PHLPP2 alleviates cytokine expression through the NLRP3/caspase-1 axis and improves depression-like behavior progression in mice

摘要

摘要:
目的： 探讨抑制PH结构域富含亮氨酸重复序列的蛋白磷酸酶2（PHLPP2）通过NLRP3/caspase-1轴减轻炎症因子表达从而改善小鼠抑郁样行为进展的分子机制。
方法： 将雄性C57BL/6J小鼠随机分为正常对照组（NC组）、小鼠慢性不可预知应激模型（CUMS）组、CUMS + NSC45586（PHLPP2抑制剂）组、CUMS + 氟西汀组，各5只。按照CUMS构建方法进行模型构建，各组灌胃给予相应药物。采用蔗糖偏好、强迫游泳、悬尾、旷场实验检测各组小鼠行为改变；ELISA法检测各组小鼠脑组织中肿瘤坏死因子（TNF）-α、白细胞介素（IL）-1β、IL-18和IL-6水平；PCR检测小鼠脑组织中PHLPP2、NLRP3、caspase-1表达。
结果： 相较于NC组，CUMS组小鼠蔗糖偏好率、直立次数、穿越平台次数均降低（P ＜ 0.05），而悬尾不动、强迫游泳时间均延长（P ＜ 0.05）；而相较于CUMS组，CUMS + NSC45586组和CUMS + 氟西汀组小鼠蔗糖偏好率、直立次数、穿越平台次数均增高，悬尾不动、强迫游泳时间均缩短（P ＜ 0.05）。ELISA实验显示，相较于NC组，CUMS组TNF-α、IL-1β、IL-18和IL-6表达均升高（P ＜ 0.05）；而相较于CUMS组，CUMS + NSC45586组和CUMS + 氟西汀组TNF-α、IL-1β、IL-18、IL-6表达均降低（P ＜ 0.05）。PCR结果显示，相较于NC组，CUMS组PHLPP2、NLRP3、caspase-1表达均升高（P ＜ 0.05）；而相较于CUMS组，CUMS + NSC45586组和CUMS + 氟西汀组PHLPP2、NLRP3、caspase-1表达均降低（P ＜ 0.05）。
结论： 抑制PHLPP2通过NLRP3/caspase-1轴减轻炎症因子表达，从而改善小鼠抑郁样行为进展。

Abstract:
Objective To investigate the molecular mechanism by which inhibition of PHLPP2 alleviates the expression of inflammatory factors through the NLRP3/caspase-1 axis, thereby improving the progression of depression-like behavior in rats.
Methods Male C57BL/6J mice were randomly divided into normal control group (NC group), mouse chronic unpredictable stress model (CUMS group), CUMS + NSC45586 group (PHLPP2 inhibitor group) and CUMS + fluoxetine group, with 5 mice in each group. The model was constructed according to CUMS construction method, and the corresponding drugs were given to each group by intragastric administration. Sucrose preference, forced swimming, tail hanging and open field tests were performed to detect the behavioral changes of mice in each group. The levels of inflammatory mediators (TNF-α, IL-1β, IL-18 and IL-6) in brain tissue of mice in each group were detected by ELISA. The expression of PHLPP2, NLRP3 and caspase-1 in brain tissue was detected by PCR.
Results Compared with the NC group, the sugar water preference rate, upright times and crossing platform times of CUMS group were significantly decreased (P ＜ 0.05), while the suspended tail immobile time and forced swimming time were extended (P ＜ 0.05). Compared with CUMS group, mice in CUMS + NSC45586 group and CUMS + fluoxetine group had increased sugar-water preference rate, upright times and platform crossing times, and decreased tail suspension immobility time and forced swimming time (P ＜ 0.05). ELISA showed that compared with NC group, the contents of TNF-α, IL-1β, IL-18 and IL-6 in CUMS group were increased (P ＜ 0.05). Compared with CUMS group, the contents of TNF-α, IL-1β, IL-18 and IL-6 in CUMS + NSC45586 group and CUMS + fluoxetine group were decreased (P ＜ 0.05). PCR results showed that compared with NC group, the expressions of PHLPP2, NLRP3 and caspase-1 in CUMS group were increased (P ＜ 0.05). Compared with CUMS group, PHLPP2, NLRP3 and caspase-1 in CUMS + NSC45586 group and CUMS + fluoxetine group were decreased (P ＜ 0.05).
Conclusion Inhibition of PHLPP2 alleviates the expression of inflammatory factors through NLRP3/caspase-1 axis and improves depression-like behavior progression in rats.

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