Treadmill exercise improves cerebral ischemia injury by regulating microglia polarization via downregulation of MMP12.

Autor: Zhang S; Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Techonology, Wuhan, China., Fan Y; Department of Neurology, Zhongnan Hospital, Wuhan University, Wuhan, China., Cao X; Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Techonology, Wuhan, China., Deng C; Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Techonology, Wuhan, China., Xu J; Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Techonology, Wuhan, China., Zhou Q; Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Techonology, Wuhan, China., Li Y; Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Techonology, Wuhan, China., Yin Y; Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Techonology, Wuhan, China. Electronic address: ytyin@tjh.tjmu.edu.cn., Chen H; Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Techonology, Wuhan, China. Electronic address: chenhong4129@hust.edu.cn.
Jazyk: angličtina
Zdroj: International immunopharmacology [Int Immunopharmacol] 2024 Dec 05; Vol. 142 (Pt B), pp. 113210. Date of Electronic Publication: 2024 Sep 27.
DOI: 10.1016/j.intimp.2024.113210
Abstrakt: Backgroud: Exercise training is the main strategy for stroke rehabilitation, and it has shown that shifting microglia toward M2 phenotype is beneficial for the recovery of neurological function after stroke. The mechanisms governing exercise training and inflammatory response after cerebral ischemia remain largely unexplored. Herein, the aim of this study was to investigate the role of exercise training in immune response after cerebral ischemia.
Methods: The transient middle cerebral artery occlusion (MCAO) rat model and primary microglia under oxygen-glucose deprivation/reoxygenation (OGD/R) conditions were used to mimic the ischemic stroke in vivo and in vitro respectively. Treadmill exercise with gradually increased intensity was initiated the second day after MCAO for a maximum of 14 days. The beam balance test, forelimb placement test, cornering test, modified adhesive removal test were used to assess the behavioral recovery. The right peri-infarct cortex was taken from 3 rats per group for RNA sequencing (RNA-seq) analysis. Real-time PCR, western blot, immunofluorescence, and phagocytosis assay was performed after MCAO and/or OGD/R.
Results: Treadmill exercise could significantly improve behavioral outcomes and reduce the infarct volumes. In addition, treadmill exercise switched microglia polarization toward M2 phenotype (Iba + /CD206 + ) in the peri-infarct cortex, and significantly increased the levels of anti-inflammatory factors (TGF-β, IL10, Arg-1, CD206) and decreased a pool of pro-inflammatory factors (IL-1β, IL-6, TNF-α, iNOS, CD68) in the peri-infarct areas. RNA-seq analysis and further studies demonstrated that exercise training could significantly reduce the expression of MMP12. Through further immunofluorescence co-labeling analysis, we found that treadmill exercise predominantly reduced the expression of MMP-12 in microglia but not in neuron after MCAO. In primary microglia after OGD/R, MMP12 inhibition switched microglia polarization toward to M2 phenotype, increased the expression of M2 markers, and enhanced its phagocytic capacities.
Conclusions: Our data demonstrate that treadmill exercise could improve the inflammatory microenvironment in the brain after ischemic stroke, which may be caused by inhibition of MMP12 expression. MMP12 suppression in primary microglia could remodel microglia immune functions. In summary, this study may provide novel insights into the immune mechanism of exercise training for stroke and suggests potential targets for therapeutic approaches.
Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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