mtDNA-STING Axis Mediates Microglial Polarization via IRF3/NF-κB Signaling After Ischemic Stroke.

Area of Science:

• Neuroscience
• Immunology
• Pathology

Background:

• Neuroinflammation, marked by microglial activation, follows ischemic stroke.
• Stimulator of interferon genes (STING) is implicated in immunity and inflammation, but its role in stroke-related microglial polarization is unclear.

Purpose of the Study:

• To investigate the role and mechanisms of STING in microglial polarization after ischemic stroke.
• To evaluate the therapeutic potential of STING inhibition in a mouse model of ischemic stroke.

Main Methods:

• Used middle cerebral artery occlusion (MCAO) in mice and oxygen-glucose deprivation/reperfusion (OGD/R) in BV2 microglia.
• Administered the STING inhibitor C-176 post-MCAO.
• Analyzed microglial polarization, brain injury markers, neurological function, and downstream signaling pathways (IRF3, NF-κB).

Main Results:

• Microglial STING expression increased after ischemic injury (MCAO and OGD/R).
• C-176 treatment reduced brain infarction, edema, neuronal injury, and improved neurological/cognitive function.
• STING promoted M1 microglial polarization and inhibited M2 polarization via IRF3 and NF-κB pathways.
• Released mitochondrial DNA (mtDNA) activated STING, driving M1 polarization; C-176 blocked these effects.

Conclusions:

• STING, activated by mtDNA, promotes detrimental M1 microglial polarization post-ischemic stroke.
• Inhibiting STING represents a promising therapeutic approach for mitigating neuroinflammation and brain damage after stroke.