Microglial VPS35 deficiency regulates microglial polarization and decreases ischemic stroke-induced damage in the cortex
Abstract Background Vacuolar sorting protein 35 (VPS35), a critical component of retromer, is essential for selective endosome-to-Golgi retrieval of membrane proteins. It is highly expressed in microglial cells, in addition to neurons. We have previously demonstrated microglial VPS35’s functions in...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2019-11-01
|
| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-019-1633-y |
| _version_ | 1818941973786001408 |
|---|---|
| author | Shi-Yang Ye Joanna E. Apple Xiao Ren Fu-Lei Tang Ling-Ling Yao Yong-Gang Wang Lin Mei Yuan-Guo Zhou Wen-Cheng Xiong |
| author_facet | Shi-Yang Ye Joanna E. Apple Xiao Ren Fu-Lei Tang Ling-Ling Yao Yong-Gang Wang Lin Mei Yuan-Guo Zhou Wen-Cheng Xiong |
| author_sort | Shi-Yang Ye |
| collection | DOAJ |
| description | Abstract Background Vacuolar sorting protein 35 (VPS35), a critical component of retromer, is essential for selective endosome-to-Golgi retrieval of membrane proteins. It is highly expressed in microglial cells, in addition to neurons. We have previously demonstrated microglial VPS35’s functions in preventing hippocampal, but not cortical, microglial activation, and in promoting adult hippocampal neurogenesis. However, microglial VPS35’s role in the cortex in response to ischemic stroke remains largely unclear. Methods We used mice with VPS35 cKO (conditional knockout) in microglial cells and examined and compared their responses to ischemic stroke with control mice. The brain damage, cell death, changes in glial cells and gene expression, and sensorimotor deficits were assessed by a combination of immunohistochemical and immunofluorescence staining, RT-PCR, Western blot, and neurological functional behavior tests. Results We found that microglial VPS35 loss results in an increase of anti-inflammatory microglia in mouse cortex after ischemic stroke. The ischemic stroke-induced brain injury phenotypes, including brain damage, neuronal death, and sensorimotor deficits, were all attenuated by microglial VPS35-deficiency. Further analysis of protein expression changes revealed a reduction in CX3CR1 (CX3C chemokine receptor 1) in microglial VPS35-deficient cortex after ischemic stroke, implicating CX3CR1 as a potential cargo of VPS35 in this event. Conclusion Together, these results reveal an unrecognized function of microglial VPS35 in enhancing ischemic brain injury-induced inflammatory microglia, but suppressing the injury-induced anti-inflammatory microglia. Consequently, microglial VPS35 cKO mice exhibit attenuation of ischemic brain injury response. |
| first_indexed | 2024-12-20T07:04:03Z |
| format | Article |
| id | doaj.art-88e9b4225d544c6a8fcc7f7d042262e5 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-20T07:04:03Z |
| publishDate | 2019-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-88e9b4225d544c6a8fcc7f7d042262e52022-12-21T19:49:07ZengBMCJournal of Neuroinflammation1742-20942019-11-0116111510.1186/s12974-019-1633-yMicroglial VPS35 deficiency regulates microglial polarization and decreases ischemic stroke-induced damage in the cortexShi-Yang Ye0Joanna E. Apple1Xiao Ren2Fu-Lei Tang3Ling-Ling Yao4Yong-Gang Wang5Lin Mei6Yuan-Guo Zhou7Wen-Cheng Xiong8Center of Molecular Biology, State Key Laboratory of Trauma, Burn and Combined Injury, Research Institute of Surgery, Daping Hospital, Third Military Medical UniversityDepartment of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta UniversityDepartment of Neurosciences, School of Medicine, Case Western Reserve UniversityDepartment of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta UniversityDepartment of Neurosciences, School of Medicine, Case Western Reserve UniversityDepartment of Neurology, Renji Hospital, Shanghai Jiaotong UniversityDepartment of Neurosciences, School of Medicine, Case Western Reserve UniversityCenter of Molecular Biology, State Key Laboratory of Trauma, Burn and Combined Injury, Research Institute of Surgery, Daping Hospital, Third Military Medical UniversityDepartment of Neurosciences, School of Medicine, Case Western Reserve UniversityAbstract Background Vacuolar sorting protein 35 (VPS35), a critical component of retromer, is essential for selective endosome-to-Golgi retrieval of membrane proteins. It is highly expressed in microglial cells, in addition to neurons. We have previously demonstrated microglial VPS35’s functions in preventing hippocampal, but not cortical, microglial activation, and in promoting adult hippocampal neurogenesis. However, microglial VPS35’s role in the cortex in response to ischemic stroke remains largely unclear. Methods We used mice with VPS35 cKO (conditional knockout) in microglial cells and examined and compared their responses to ischemic stroke with control mice. The brain damage, cell death, changes in glial cells and gene expression, and sensorimotor deficits were assessed by a combination of immunohistochemical and immunofluorescence staining, RT-PCR, Western blot, and neurological functional behavior tests. Results We found that microglial VPS35 loss results in an increase of anti-inflammatory microglia in mouse cortex after ischemic stroke. The ischemic stroke-induced brain injury phenotypes, including brain damage, neuronal death, and sensorimotor deficits, were all attenuated by microglial VPS35-deficiency. Further analysis of protein expression changes revealed a reduction in CX3CR1 (CX3C chemokine receptor 1) in microglial VPS35-deficient cortex after ischemic stroke, implicating CX3CR1 as a potential cargo of VPS35 in this event. Conclusion Together, these results reveal an unrecognized function of microglial VPS35 in enhancing ischemic brain injury-induced inflammatory microglia, but suppressing the injury-induced anti-inflammatory microglia. Consequently, microglial VPS35 cKO mice exhibit attenuation of ischemic brain injury response.http://link.springer.com/article/10.1186/s12974-019-1633-yVPS35MicrogliaIschemic brain injuryCX3CR1 |
| spellingShingle | Shi-Yang Ye Joanna E. Apple Xiao Ren Fu-Lei Tang Ling-Ling Yao Yong-Gang Wang Lin Mei Yuan-Guo Zhou Wen-Cheng Xiong Microglial VPS35 deficiency regulates microglial polarization and decreases ischemic stroke-induced damage in the cortex Journal of Neuroinflammation VPS35 Microglia Ischemic brain injury CX3CR1 |
| title | Microglial VPS35 deficiency regulates microglial polarization and decreases ischemic stroke-induced damage in the cortex |
| title_full | Microglial VPS35 deficiency regulates microglial polarization and decreases ischemic stroke-induced damage in the cortex |
| title_fullStr | Microglial VPS35 deficiency regulates microglial polarization and decreases ischemic stroke-induced damage in the cortex |
| title_full_unstemmed | Microglial VPS35 deficiency regulates microglial polarization and decreases ischemic stroke-induced damage in the cortex |
| title_short | Microglial VPS35 deficiency regulates microglial polarization and decreases ischemic stroke-induced damage in the cortex |
| title_sort | microglial vps35 deficiency regulates microglial polarization and decreases ischemic stroke induced damage in the cortex |
| topic | VPS35 Microglia Ischemic brain injury CX3CR1 |
| url | http://link.springer.com/article/10.1186/s12974-019-1633-y |
| work_keys_str_mv | AT shiyangye microglialvps35deficiencyregulatesmicroglialpolarizationanddecreasesischemicstrokeinduceddamageinthecortex AT joannaeapple microglialvps35deficiencyregulatesmicroglialpolarizationanddecreasesischemicstrokeinduceddamageinthecortex AT xiaoren microglialvps35deficiencyregulatesmicroglialpolarizationanddecreasesischemicstrokeinduceddamageinthecortex AT fuleitang microglialvps35deficiencyregulatesmicroglialpolarizationanddecreasesischemicstrokeinduceddamageinthecortex AT linglingyao microglialvps35deficiencyregulatesmicroglialpolarizationanddecreasesischemicstrokeinduceddamageinthecortex AT yonggangwang microglialvps35deficiencyregulatesmicroglialpolarizationanddecreasesischemicstrokeinduceddamageinthecortex AT linmei microglialvps35deficiencyregulatesmicroglialpolarizationanddecreasesischemicstrokeinduceddamageinthecortex AT yuanguozhou microglialvps35deficiencyregulatesmicroglialpolarizationanddecreasesischemicstrokeinduceddamageinthecortex AT wenchengxiong microglialvps35deficiencyregulatesmicroglialpolarizationanddecreasesischemicstrokeinduceddamageinthecortex |