KDM4A regulates microglial polarization after ischemic stroke by regulating SPINK5 signaling

Area of Science:

• Neuroscience
• Molecular Biology
• Immunology

Background:

• Microglia/macrophage polarization is critical in ischemic stroke (IS) inflammation.
• Understanding the molecular regulation of this process is key to developing new therapies.

Purpose of the Study:

• To investigate the role of lysine-specific histone demethylase 4A (KDM4A) in regulating microglial polarization post-ischemic stroke.
• To elucidate the molecular mechanisms underlying KDM4A's function in ischemic stroke.

Main Methods:

• Established in vivo (MCAO) and in vitro (OGD) models of ischemic stroke.
• Utilized TTC staining, RT-qPCR, immunofluorescence, Western blot, ChIP assay, and TUNEL assay to assess infarct size, gene/protein expression, microglial polarization, and apoptosis.

Main Results:

• KDM4A was upregulated in ischemic stroke models.
• KDM4A downregulation improved neurological function, motor capacity, and reduced inflammation and pro-inflammatory microglial activation.
• KDM4A reduced H3K9me3 on the SPINK5 promoter, increasing SPINK5 expression, which in turn inhibited M2 microglial polarization and neuronal apoptosis.

Conclusions:

• KDM4A exacerbates ischemic stroke brain injury by promoting pro-inflammatory microglial polarization through the SPINK5 signaling pathway.
• Targeting KDM4A may represent a therapeutic strategy for mitigating ischemic stroke-induced brain damage.