Aerobic Exercise Inhibits CUMS-Depressed Mice Hippocampal Inflammatory Response via Activating Hippocampal miR-223/TLR4/MyD88-NF-κB Pathway

Abstract

Objective: To investigate the role of aerobic exercise in inhibiting chronic unpredictable mild stress (CUMS) depressed mice hippocampal inflammatory response and its potential mechanisms. Methods: Fifty-four male eight-week-old C57BL/6 mice were divided as control group (CG) (18 mice) and model group (36 mice). Model group mice were treated with 13 chronic stimulating factors for 28 days to set up the CUMS depression model. Neurobehavioral assessment was performed after modeling. The mice in the model group were randomly divided into the control model group (MG) and the aerobic exercise group (EG), with 18mice in each group. The EG group carried out the adaptive training of the running platform: 10 m/min, 0° slope, and increased by 10 minutes per day for 6 days. The formal training was carried for 8 weeks with 10 m/min speed, 0° slope, 60 min/d, 6 d/Week. After the training, a neurobehavioral assessment was performed, and hippocampus IL-1β and IL-10 protein levels were detected by ELISA. RT–PCR was used to detect the expression of miR-223 and TLR4, MyD88, and NF-κB in the hippocampus. Western blot was used to detect the expression of TLR4 and phosphorylated NF-κBp65 protein in the hippocampus. Results: The hippocampus function of CUMS depression model mice was impaired. The forced swimming and forced tail suspension time were significantly prolonged, and inflammatory factors IL-1β were significantly increased in the hippocampus. Aerobic exercise significantly improves CUMS-depressed mice hippocampal function, effectively reducing depressive behavior and IL-1β levels, and increasing IL-10 levels. Besides, aerobic exercise significantly upregulates the expression level of miR-223 and inhibits the high expression of TLR4, MyD88, and NF-κB. Conclusion: Aerobic exercise significantly increases the CUMS-depressed mice hippocampus expression of miR-223, and inhibits the downstream TLR4/MyD88-NF-κB signaling pathway and the hippocampal inflammatory response, which contributes to the improvement of the hippocampal function.

The Role of MicroRNA and Microbiota in Depression and Anxiety

“…In addition, it has been reported that regular physical exercise can change the levels of miRNAs ( Bye et al, 2013 ). Aerobic exercise increases the expression of miR-223 while reducing TLR4, MyD88, and NF-κB levels ( Qu et al, 2020 ). Mice exposed to chronic stress have shown increased hippocampal levels of miR-223, which are reduced by 8 weeks of treadmill running ( Qu et al, 2020 ).…”

“…Aerobic exercise increases the expression of miR-223 while reducing TLR4, MyD88, and NF-κB levels ( Qu et al, 2020 ). Mice exposed to chronic stress have shown increased hippocampal levels of miR-223, which are reduced by 8 weeks of treadmill running ( Qu et al, 2020 ). Moreover, 4 weeks of treadmill running increases the expression levels of miR-129-1-3p, miR-144-5p, and miR-10b-5p in the hippocampus ( Fernandes et al, 2018 ).…”

miR-223: An Effective Regulator of Immune Cell Differentiation and Inflammation

“…In vitro experiments also demonstrated that decreased miR-223 expression resulted in diminished inhibition of RHOB, NLRP3 inflammasome and TLR4/NF-κB pathway, exacerbating lung injury ( Figure 7 ) 72 , 85 . In a mouse study of hippocampal inflammation, aerobic exercise can induce miR-223 expression in the hippocampus, which negatively regulates the TLR4/MyD88-NF-κB pathway to improve inflammation-induced injury 86 . miR-223 can also alleviate neutrophilic airway inflammation by inhibiting NLRP3 inflammasome and IL-1β release 87 .…”

MicroRNAs as Critical Biomarkers of Major Depressive Disorder: A Comprehensive Perspective

“…Preclinical studies and then clinical studies corroborate that physical therapy is a perfect non-pharmacological adjuvant. CUMS depressed mice subdued to aerobic exercise have shown increased hippocampus expression of miR-223 and inhibition the TLR4/MyD88-NFκB signaling pathway and associated-inflammatory response, IL-1β levels, and increasing IL-10 levels [ 249 ]. These neuroimmunomodulatory effects have been confirmed in MDD patients: the downregulation of proinflammatory cytokines, M1 microglia and reactive astrocytes [ 250 , 251 ].…”