Based on the IL-33/ST2-MyD88 signaling pathway to explore the mechanism of aerobic exercise in antagonizing the inflammatory response in depressive mice

Abstract

Purpose

This study examined how aerobic exercise affect the IL-33/ST2-MyD88 signaling pathway in mice with chronic unpredictable mild stress (CUMS) induced depression

Method

Thirty-six C57BL/6 mice were randomly assigned t three groups: a control group (CG), a model group (MG), and an exercise group (ME). We created a depression model using chronic unpredictable mild stress, after which the ME group underwent 8 weeks of aerobic training. After exercise intervention, neurobehavioral assessment was performed. ELISA was used to detect the levels of IL-33, IL-1β and IL-10 in the serum of mice. Toluidine blue Nissl staining was used to observe the structure of hippocampal neurons. Total RNA was extracted from blood samples using magnetic beads and from hippocampal tissue or neurons using Trizol. The levels of IL-33, ST2, MyD88, IL-1β, IL-10 and NF-κB mRNA in mice were detected by RT-PCR

Result

The number of lattice crossings and modification times were significantly reduced in MG group, the exercise time was significantly shortened, and the sugar and water preference index was significantly reduced, while the immobility time in forced swimming and tail suspension tests were significantly prolonged. The results indicated that CUMS successfully induced anhedonia and depression-like behaviors in the mice. In the ME group, there was a significant increase in the number of crossing lattices, modification times, exercise duration, and sugar and water preference index, while the immobility time in the forced swimming and tail suspension tests significantly decreased. Compared with the CG group, serum levels of inflammatory factors IL-33, IL-1β, and NF-κB significantly increased in the MG group, while these levels significantly decreased in the ME group. It decreased and IL-10 showed a very significant increase. Nissl staining results indicated that hippocampal nerve cells in MG group were sparsely arranged, with widened gaps, severe nucleus contraction, and shallow staining. The ME group had reduced neuronal vacuoles and improved nuclear shrinkage. Immunohistochemical results revealed that in MG group, the expression of pro-inflammatory factors IL-1β and MyD88 increased. In Contrast, the ME group exhibited a decrease in IL-1β and MyD88, alongside a significant increase in the anti-inflammatory factor IL-10. In the RT-PCR test results, the blood inflammation signal pathway IL-33/ST2 and its downstream factors MyD88, NF-κB, and IL-1β mRNA were significantly up-regulated, and the inhibitory factor IL-10 mRNA was up-regulated in MG group. Gene expression trends for IL-33 mRNA, ST2 mRNA, IL-1β mRNA, MyD88 mRNA and NF-κB mRNA in hippocampus tissue were similar to those in blood, all showing significant up-regulation. In contrast, IL-10 mRNA did not exhibit significant up-regulation. While IL-33/ST2 expression did not significantly decrease, other pro-inflammatory factors showed significant down-regulation, and anti-inflammatory factors demonstrated significant up-regulated. Similarly, IL-33 mRNA, ST2 mRNA and MyD88 mRNA expressions in the hippocampus of ME mice mirrored the changes observed in blood when compared to MG mice. NF-κB mRNA was significantly down-regulated, while IL-1β mRNA showed no significant change, and IL-10 mRNA was up-regulated, albeit not significantly.

Conclusion

Aerobic exercise may counteract the CUMS depression model in mice by regulating the IL-33/ST2-MyD88 signaling pathway. The strong correlation of inflammatory cytokines between blood and hippocampus indicated that assessing inflammatory damage in the hippocampus could be done through blood tests of the signaling pathway and related cytokine levels.