STING inhibition alleviates post-cardiac arrest brain injury by suppressing microglia-mediated neuroinflammation via the cGAS/STING/NF-κB pathway.
TL;DR
The findings suggest that STING is a promising therapeutic target for reducing neuroinflammation and neuronal damage, ultimately contributing to the alleviation of brain injury after CA.
Abstract
Background
Neuroinflammation plays a pivotal role in the pathogenesis of brain injury following cardiac arrest(CA), primarily mediated by microglial activation. The stimulator of interferon genes (STING) has been demonstrated to play a pivotal role in regulating anti-tumor immunity and inflammatory diseases. However, the functional impact and underlying mechanisms of STING in regulating microglial polarization following brain injury after cardiac arrest remain poorly understood.
Methods
In this study, we employed an in vivo model of hyperkalemic cardiac arrest and an in vitro BV2 microglial oxygen-glucose deprivation/reperfusion (OGD/R) model to simulate brain injury following cardiac arrest (CA). STING was specifically inhibited using H151 or gene silencing. A range of techniques, including neurological function scoring, RNA sequencing, western blotting, immunofluorescence, FJB and TUNEL staining, HE and Nissl staining, ELISA, and flow cytometry, were applied in both in vivo and in vitro settings to evaluate the outcomes.
Results
We observed that STING expression in microglia was significantly upregulated following CA or OGD/R. Pharmacological inhibition of STING with H151 improves survival rate and neurological function in mice following CA and attenuates neuronal degeneration and apoptosis. Furthermore, H151 induces a phenotypic shift in microglia from the pro-inflammatory M1 state to the anti-inflammatory M2 state. These results are also associated with reduced production of pro-inflammatory cytokines, including IL-6 and TNF-α, as well as increased levels of anti-inflammatory cytokines such as IL-10 and TGF-β. Mechanistically, both in vivo and in vitro experiments demonstrate that STING activation promotes microglial polarization toward the pro-inflammatory M1 phenotype while suppressing the anti-inflammatory M2 phenotype through downstream signaling pathways involving interferon regulatory factor 3 and nuclear factor κB (NF-κB). Conversely, inhibition of STING-achieved either pharmacologically using the inhibitor H151 or genetically via gene silencing-results in the opposite effects.
Conclusions
Inhibition of the cGAS/STING/NF-κB signaling pathway shifts microglial polarization toward the M2 phenotype, thereby attenuating neuroinflammation, as well as neuronal degeneration and apoptosis. These findings suggest that STING is a promising therapeutic target for reducing neuroinflammation and neuronal damage, ultimately contributing to the alleviation of brain injury after CA.