TREM2 mediates physical exercise-promoted neural functional recovery in rats with ischemic stroke via microglia-promoted white matter repair
Abstract Background The repair of white matter injury is of significant importance for functional recovery after ischemic stroke, and the up-regulation of triggering receptors expressed on myeloid cells 2 (TREM2) after ischemic stroke is neuroprotective and implicated in remyelination. However, the...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-02-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-023-02741-w |
| _version_ | 1797864058669498368 |
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| author | Jinghui Xu Liying Zhang Mingyue Li Xiaofei He Jing Luo Rui Wu Zhongqiu Hong Haiqing Zheng Xiquan Hu |
| author_facet | Jinghui Xu Liying Zhang Mingyue Li Xiaofei He Jing Luo Rui Wu Zhongqiu Hong Haiqing Zheng Xiquan Hu |
| author_sort | Jinghui Xu |
| collection | DOAJ |
| description | Abstract Background The repair of white matter injury is of significant importance for functional recovery after ischemic stroke, and the up-regulation of triggering receptors expressed on myeloid cells 2 (TREM2) after ischemic stroke is neuroprotective and implicated in remyelination. However, the lack of effective therapies calls for the need to investigate the regenerative process of remyelination and the role of rehabilitation therapy. This study sought to investigate whether and how moderate physical exercise (PE) promotes oligodendrogenesis and remyelination in rats with transient middle cerebral artery occlusion (tMCAO). Methods Male Sprague–Dawley rats (weighing 250–280 g) were subjected to tMCAO. AAV-shRNA was injected into the lateral ventricle to silence the Trem2 gene before the operation. The rats in the physical exercise group started electric running cage training at 48 h after the operation. The Morris water maze and novel object recognition test were used to evaluate cognitive function. Luxol fast blue staining, diffusion tensor imaging, and electron microscopy were used to observe myelin injury and repair. Immunofluorescence staining was applied to observe the proliferation and differentiation of oligodendrocyte precursor cells (OPCs). Expression of key molecules were detected using immunofluorescence staining, quantitative real-time polymerase chain reaction, Western blotting, and Enzyme-linked immunosorbent assay, respectively. Results PE exerted neuroprotective efects by modulating microglial state, promoting remyelination and recovery of neurological function of rats over 35 d after stroke, while silencing Trem2 expression in rats suppressed the aforementioned effects promoted by PE. In addition, by leveraging the activin-A neutralizing antibody, we found a direct beneficial effect of PE on microglia-derived activin-A and its subsequent role on oligodendrocyte differentiation and remyelination mediated by the activin-A/Acvr axis. Conclusions The present study reveals a novel regenerative role of PE in white matter injury after stroke, which is mediated by upregulation of TREM2 and microglia-derived factor for oligodendrocytes regeneration. PE is an effective therapeutic approach for improving white matter integrity and alleviating neurological function deficits after ischemic stroke. |
| first_indexed | 2024-04-09T22:45:27Z |
| format | Article |
| id | doaj.art-ffc47be2bd5b43b486f0df0b6f6d7115 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-09T22:45:27Z |
| publishDate | 2023-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-ffc47be2bd5b43b486f0df0b6f6d71152023-03-22T11:55:13ZengBMCJournal of Neuroinflammation1742-20942023-02-0120111810.1186/s12974-023-02741-wTREM2 mediates physical exercise-promoted neural functional recovery in rats with ischemic stroke via microglia-promoted white matter repairJinghui Xu0Liying Zhang1Mingyue Li2Xiaofei He3Jing Luo4Rui Wu5Zhongqiu Hong6Haiqing Zheng7Xiquan Hu8Department of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-Sen UniversityDepartment of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-Sen UniversityDepartment of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-Sen UniversityDepartment of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-Sen UniversityDepartment of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-Sen UniversityDepartment of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-Sen UniversityDepartment of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-Sen UniversityDepartment of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-Sen UniversityDepartment of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-Sen UniversityAbstract Background The repair of white matter injury is of significant importance for functional recovery after ischemic stroke, and the up-regulation of triggering receptors expressed on myeloid cells 2 (TREM2) after ischemic stroke is neuroprotective and implicated in remyelination. However, the lack of effective therapies calls for the need to investigate the regenerative process of remyelination and the role of rehabilitation therapy. This study sought to investigate whether and how moderate physical exercise (PE) promotes oligodendrogenesis and remyelination in rats with transient middle cerebral artery occlusion (tMCAO). Methods Male Sprague–Dawley rats (weighing 250–280 g) were subjected to tMCAO. AAV-shRNA was injected into the lateral ventricle to silence the Trem2 gene before the operation. The rats in the physical exercise group started electric running cage training at 48 h after the operation. The Morris water maze and novel object recognition test were used to evaluate cognitive function. Luxol fast blue staining, diffusion tensor imaging, and electron microscopy were used to observe myelin injury and repair. Immunofluorescence staining was applied to observe the proliferation and differentiation of oligodendrocyte precursor cells (OPCs). Expression of key molecules were detected using immunofluorescence staining, quantitative real-time polymerase chain reaction, Western blotting, and Enzyme-linked immunosorbent assay, respectively. Results PE exerted neuroprotective efects by modulating microglial state, promoting remyelination and recovery of neurological function of rats over 35 d after stroke, while silencing Trem2 expression in rats suppressed the aforementioned effects promoted by PE. In addition, by leveraging the activin-A neutralizing antibody, we found a direct beneficial effect of PE on microglia-derived activin-A and its subsequent role on oligodendrocyte differentiation and remyelination mediated by the activin-A/Acvr axis. Conclusions The present study reveals a novel regenerative role of PE in white matter injury after stroke, which is mediated by upregulation of TREM2 and microglia-derived factor for oligodendrocytes regeneration. PE is an effective therapeutic approach for improving white matter integrity and alleviating neurological function deficits after ischemic stroke.https://doi.org/10.1186/s12974-023-02741-wIschemic strokePhysical exerciseTriggering receptor expressed on myeloid cells 2Brain white matter repairMicroglia |
| spellingShingle | Jinghui Xu Liying Zhang Mingyue Li Xiaofei He Jing Luo Rui Wu Zhongqiu Hong Haiqing Zheng Xiquan Hu TREM2 mediates physical exercise-promoted neural functional recovery in rats with ischemic stroke via microglia-promoted white matter repair Journal of Neuroinflammation Ischemic stroke Physical exercise Triggering receptor expressed on myeloid cells 2 Brain white matter repair Microglia |
| title | TREM2 mediates physical exercise-promoted neural functional recovery in rats with ischemic stroke via microglia-promoted white matter repair |
| title_full | TREM2 mediates physical exercise-promoted neural functional recovery in rats with ischemic stroke via microglia-promoted white matter repair |
| title_fullStr | TREM2 mediates physical exercise-promoted neural functional recovery in rats with ischemic stroke via microglia-promoted white matter repair |
| title_full_unstemmed | TREM2 mediates physical exercise-promoted neural functional recovery in rats with ischemic stroke via microglia-promoted white matter repair |
| title_short | TREM2 mediates physical exercise-promoted neural functional recovery in rats with ischemic stroke via microglia-promoted white matter repair |
| title_sort | trem2 mediates physical exercise promoted neural functional recovery in rats with ischemic stroke via microglia promoted white matter repair |
| topic | Ischemic stroke Physical exercise Triggering receptor expressed on myeloid cells 2 Brain white matter repair Microglia |
| url | https://doi.org/10.1186/s12974-023-02741-w |
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