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HDAC3 inhibition ameliorates ischemia/reperfusion-induced brain injury by regulating the microglial cGAS-STING pathway
- Source :
- Theranostics
- Publication Year :
- 2020
- Publisher :
- Ivyspring International Publisher, 2020.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 18387640
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- Theranostics
- Accession number :
- edsair.doi.dedup.....8ff6a214fc937ea198f3003e976cd295