Microglial VPS35 deficiency regulates microglial polarization and decreases ischemic stroke-induced damage in the cortex
| Autor: | Lin Mei, Joanna E. Apple, Ling Ling Yao, Yonggang Wang, Wen Cheng Xiong, Fu Lei Tang, Yuan Guo Zhou, Shi Yang Ye, Xiao Ren |
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| Rok vydání: | 2019 |
| Předmět: |
Programmed cell death
Immunology CX3C Chemokine Receptor 1 Vesicular Transport Proteins Brain damage Hippocampal formation lcsh:RC346-429 Brain Ischemia Ischemic brain injury CX3CR1 Mice 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Cortex (anatomy) Conditional gene knockout medicine Animals Gliosis VPS35 lcsh:Neurology. Diseases of the nervous system 030304 developmental biology Mice Knockout 0303 health sciences Cell Death Microglia business.industry Research General Neuroscience Neurogenesis Cell Polarity Stroke Disease Models Animal medicine.anatomical_structure Neurology Motor Skills Sensorimotor Cortex medicine.symptom business Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Journal of Neuroinflammation Journal of Neuroinflammation, Vol 16, Iss 1, Pp 1-15 (2019) |
| ISSN: | 1742-2094 |
| DOI: | 10.1186/s12974-019-1633-y |
| Popis: | BackgroundVacuolar 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.MethodsWe 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.ResultsWe 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.ConclusionTogether, 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. |
| Databáze: | OpenAIRE |
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