UNC5B Promotes Post-Stroke Microglial Pyroptosis via DAPK3/MVK Pathway

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Pyroptotic inflammation exacerbates neuronal damage following stroke.
• Uncoordinated-5 homolog B (UNC5B) is linked to neuroinflammation.
• UNC5B's downstream kinase, DAPK3, may interact with mevalonate kinase (MVK).

Purpose of the Study:

• To investigate the role of UNC5B in post-stroke pyroptosis.
• To elucidate the molecular mechanisms involving UNC5B, DAPK3, and MVK in neuronal injury.

Main Methods:

• Utilized photothrombosis (PT) stroke and oxygen-glucose deprivation (OGD) models.
• Performed Unc5b and Mvk knockdown, and DAPK3 inhibition.
• Assessed pyroptosis markers, cell viability, and DAPK3-MVK interactions via co-immunoprecipitation.

Main Results:

• PT/OGD induced neuronal injury and pyroptosis.
• Unc5b or Mvk knockdown suppressed microglial pyroptosis and protected neurons.
• Disruption of the DAPK3-MVK complex was observed.
• UNC5B knockdown or DAPK3 inhibition prevented p-MVK upregulation; only UNC5B knockdown blocked DAPK3 upregulation.

Conclusions:

• UNC5B promotes post-stroke microglial pyroptosis.
• The DAPK3/MVK pathway is a key mediator of UNC5B-induced pyroptosis.
• Targeting UNC5B or the DAPK3/MVK pathway may offer neuroprotective strategies post-stroke.