HDAC3 inhibition ameliorates ischemia/reperfusion-induced brain injury by regulating the microglial cGAS-STING pathway
Autor: | Zengqiang Yuan, Shuoshuo Li, He Zhang, Liao Yajin, Yun Xu, Xiangxi Kong, Tianli Yang, Jun Li, Yuan Dong, Jinbo Cheng, Xiaoheng Li, Meijuan Zhang |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Cell Ischemia Ischemia/reperfusion Medicine (miscellaneous) DNA Mitochondrial Histone Deacetylases Brain Ischemia Cell Line 03 medical and health sciences 0302 clinical medicine Neuroinflammation Western blot Interferon Animals Humans Medicine Pharmacology Toxicology and Pharmaceutics (miscellaneous) Inflammation Mice Knockout Neurons Innate immune system Microglia medicine.diagnostic_test business.industry Brain Membrane Proteins HDAC3 Infarction Middle Cerebral Artery medicine.disease Nucleotidyltransferases Cell biology HEK293 Cells 030104 developmental biology medicine.anatomical_structure Brain Injuries Reperfusion Injury business 030217 neurology & neurosurgery Signal Transduction Research Paper cGAS medicine.drug |
Zdroj: | Theranostics |
ISSN: | 1838-7640 |
Popis: | Rationale: It is known that neuroinflammation plays a critical and detrimental role in the development of cerebral ischemia/reperfusion (I/R), but the regulation of the cyclic GMP-AMP synthase (cGAS)-mediated innate immune response in I/R-induced neuroinflammation is largely unexplored. This study aimed to investigate the function and regulatory mechanism of cGAS in I/R-induced neuroinflammation and brain injury, and to identify possible strategies for the treatment of ischemic stroke. Methods: To demonstrate that microglial histone deacetylase 3 (HDAC3) regulates the microglial cGAS-stimulator of interferon genes (cGAS-STING) pathway and is involved in I/R-induced neuroinflammation and brain injury, a series of cell biological, molecular, and biochemical approaches were utilized. These approaches include transient middle cerebral artery occlusion (tMCAO), real-time polymerase chain reaction (PCR), RNA sequencing, western blot, co-immunoprecipitation, chromosome-immunoprecipitation, enzyme-linked immunosorbent assay (ELISA), dual-luciferase reporter assay, immunohistochemistry, and confocal imaging. Results: The microglial cGAS- STING pathway was activated by mitochondrial DNA, which promoted the formation of a pro-inflammatory microenvironment. In addition, we revealed that HDAC3 transcriptionally promoted the expression of cGAS and potentiated the activation of the cGAS-STING pathway by regulating the acetylation and nuclear localization of p65 in microglia. Our in vivo results indicated that deletion of cGAS or HDAC3 in microglia attenuated I/R-induced neuroinflammation and brain injury. Conclusion: Collectively, we elucidated that the HDAC3-p65-cGAS-STING pathway is involved in the development of I/R-induced neuroinflammation, identifying a new therapeutic avenue for the treatment of ischemic stroke. |
Databáze: | OpenAIRE |
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