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PRMT8 Attenuates Cerebral Ischemia/Reperfusion Injury via Modulating Microglia Activation and Polarization to
Kuang Zheng1, Yuliang Zhang1, Chengwei Zhang1
1Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
Abstract:
Activation and polarization of microglia are involved in neuroinflammation and regulate ischemic stroke-associated brain injury. Protein arginine methyltransferase 8 functions as a regulatory component of hypoxic stress-induced neuroinflammation. The protective effect of protein arginine methyltransferase 8 (PRMT8) against ischemic stroke-associated brain injury through regulation of microglia activation and polarization was investigated. First, PRMT8 was downregulated in middle cerebral artery occlusion (MCAO)-induced mice and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced SH-SY5Y. Injection with AAV-PRMT8 reduced infarct volumes in MCAO-induced mice. Moreover, injection with AAV-PRMT8 promoted neuronal survival and ameliorated histopathological changes in the brains of MCAO-induced mice. The neuronal apoptosis and neuroinflammation in MCAO-induced mice were suppressed by AAV-PRMT8 injection. Second, PRMT8 overexpression increased cell viability and suppressed the cell apoptosis and inflammation of OGD/R-induced SH-SY5Y. Third, injection with AAV-PRMT8 reduced almost 50% of CD86 + M1 microglia and enhanced about 20% of CD206 + M2 microglia. Furthermore, PRMT8 overexpression attenuated OGD/R-induced M1 phenotype polarization of BV2. Lastly, PRMT8 upregulated Lin28a and loss of Lin28a attenuated PRMT8 overexpression-induced increase in cell viability and decrease in cell apoptosis and inflammation of OGD/R-induced SH-SY5Y. In conclusion, PRMT8 promoted M2 phenotype polarization of microglia and suppressed neuronal apoptosis to ameliorate cerebral ischemia/reperfusion injury through upregulation of Lin28a.
Insights
Protein arginine methyltransferase 8 (PRMT8) protects against ischemic stroke by reducing brain injury. PRMT8 promotes beneficial M2 microglia polarization and suppresses neuronal apoptosis, offering a potential therapeutic target for stroke.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Microglia activation and polarization are key players in neuroinflammation and ischemic stroke-induced brain damage.
- Protein arginine methyltransferase 8 (PRMT8) is implicated in regulating hypoxic stress-induced neuroinflammation.
Purpose of the Study:
- To investigate the protective role of PRMT8 against ischemic stroke-associated brain injury.
- To explore PRMT8's mechanism involving microglia activation, polarization, and the Lin28a pathway.
Main Methods:
- Utilized middle cerebral artery occlusion (MCAO) mouse models and oxygen-glucose deprivation/reoxygenation (OGD/R) in SH-SY5Y cells.
- Employed adeno-associated virus (AAV) vectors for PRMT8 gene delivery and assessed microglia phenotypes (M1/M2) via CD86 and CD206 markers.
- Investigated the role of Lin28a in mediating PRMT8's effects.
Main Results:
- PRMT8 was downregulated in MCAO and OGD/R models; AAV-PRMT8 injection reduced infarct volume, neuronal apoptosis, and neuroinflammation.
- PRMT8 overexpression enhanced cell viability and suppressed apoptosis/inflammation in OGD/R-induced cells, shifting microglia towards an M2 phenotype.
- PRMT8 upregulated Lin28a, which was essential for PRMT8's protective effects on cell viability and apoptosis/inflammation.
Conclusions:
- PRMT8 exerts a protective effect against cerebral ischemia/reperfusion injury.
- PRMT8 ameliorates brain injury by promoting M2 microglia polarization and suppressing neuronal apoptosis, partly through Lin28a upregulation.
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