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

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.