The phenotypic transformation of astrocytes after AIS can be regulated by microglial GSDMD-mediated pyroptosis
Yige Zhang1, Yifang Zhou1, Wan Zhang1
1Department of Neurology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; NHC Key Laboratory of Prevention and treatment of Cerebrovascular Diseases, Zhengzhou, China.
Background:
Microglial pyroptosis contributes to the pathogenesis of ischemic stroke through multiple pathways. However, it is unclear how it contributes to the phenotype switching of neuroinflammatory/ neuroprotective astrocytes.
Methods:
This study established a mouse MCAO model and utilized microglial Gsdmd gene knockout mice to examine neuroinflammatory/neuroprotective astrocyte-related protein expression, infarct volume, mNSS scores, and other metrics. Additionally, a transwell co-culture model of microglia and astrocytes was constructed, followed by treatment with IL-1β, pyroptosis inhibitor DSF, and IL-1R1 inhibitor IL-1RA.
Results:
The findings confirm that microglial GSDMD protein-mediated pyroptosis influences the phenotypic transformation of neuroinflammatory/neuroprotective astrocytes. Specifically, GSDMD-mediated pyroptosis in microglia releases IL-1β, which binds to the IL-1R1 receptor, reversing neuroinflammatory / neuroprotective astrocyte polarization.
Conclusion:
This mechanism improves AIS prognosis and may serve as a promising therapeutic candidate in AIS.
Insights
Microglial pyroptosis, driven by GSDMD, influences astrocyte behavior in ischemic stroke. This pathway, involving IL-1β, offers a potential therapeutic target for acute ischemic stroke (AIS).
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Microglial pyroptosis is implicated in ischemic stroke pathogenesis.
- Its role in neuroinflammatory and neuroprotective astrocyte phenotype switching remains unclear.
Purpose of the Study:
- To investigate the role of microglial pyroptosis in astrocyte phenotype switching during ischemic stroke.
- To elucidate the specific mechanisms involved in this interaction.
Main Methods:
- Established a mouse middle cerebral artery occlusion (MCAO) model and used Gsdmd gene knockout mice.
- Employed transwell co-culture systems with microglia and astrocytes.
- Administered treatments including IL-1β, pyroptosis inhibitor DSF, and IL-1R1 inhibitor IL-1RA.
Main Results:
- Microglial GSDMD-mediated pyroptosis directly impacts astrocyte phenotypic transformation.
- Pyroptosis releases IL-1β, which binds to IL-1R1, altering astrocyte polarization.
- This interaction influences neuroinflammatory and neuroprotective states.
Conclusions:
- The identified mechanism involving microglial pyroptosis and astrocyte interaction improves acute ischemic stroke (AIS) prognosis.
- This pathway presents a potential therapeutic strategy for AIS treatment.
