METTL3 inhibition alleviates neuroinflammation and apoptosis by reducing ETV4 m6A modification

Area of Science:

• Neuroscience
• Epigenetics
• Immunology

Background:

• Intracerebral hemorrhage (ICH) causes secondary brain injury via microglial activation and neuroinflammation.
• The role of N6-methyladenosine (m6A) RNA methylation in ICH microglia is not well understood.

Purpose of the Study:

• To investigate the role of METTL3 in microglial activation and neuroinflammation following ICH.
• To elucidate the molecular mechanisms by which METTL3 influences ICH pathology.

Main Methods:

• Utilized a mouse model of ICH.
• Analyzed METTL3 expression in microglia.
• Performed functional studies involving METTL3 depletion.
• Employed MeRIP-seq and RNA-seq to identify molecular targets.
• Assessed cytokine release, NF-κB activation, and apoptosis.

Main Results:

• METTL3 expression was upregulated in microglia in ICH model mice, correlating with increased m6A levels.
• METTL3 depletion reduced proinflammatory cytokine release (TNF-α, IL-1β, IL-6), suppressed NF-κB activation, and decreased microglial apoptosis.
• Identified ETV4 as a METTL3 target; METTL3-mediated m6A modification of ETV4 mRNA increased its stability via IGF2BP2 recruitment.
• This pathway promoted NF-κB-mediated inflammation and caspase-3-dependent apoptosis.

Conclusions:

• METTL3 acts as a key epigenetic driver of neuropathology in ICH by sustaining neuroinflammation and apoptosis.
• The METTL3/m6A/ETV4/IGF2BP2 axis is crucial for ICH progression.
• Targeting METTL3 presents a potential therapeutic strategy for mitigating ICH-induced brain injury.