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The transcription factor MEF2C restrains microglial overactivation by inhibiting kinase CDK2

Xiaodan Hu1, Jianchen Wu1, Lu Shi2

  • 1New Cornerstone Science Laboratory, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.

Immunity
|March 26, 2025
PubMed

Insights

Microglial immune checkpoints prevent overactivation in neurological disorders. MEF2C loss causes overactivation, but CDK2 inhibition with BMS265246 restores homeostasis, offering a therapeutic target for neuroinflammation.

Area of Science:

  • Neuroscience
  • Immunology
  • Genetics

Background:

  • Microglial immune checkpoints are vital for preventing overactivation and maintaining immune homeostasis.
  • Microglial overactivation is implicated in neurological disorders, including autism spectrum disorder (ASD).
  • MEF2C is a key immune checkpoint regulating microglial activation, but its precise mechanism is not fully understood.

Purpose of the Study:

  • To elucidate the mechanism by which MEF2C regulates microglial activation.
  • To identify potential therapeutic targets for microglial overactivation in neuroinflammatory conditions.

Main Methods:

  • Utilized human pluripotent stem cell-derived microglia-like cells (iMGLs) from MEF2C-deficient (MEF2C-/-) and wild-type backgrounds.
  • Performed high-throughput screening to identify compounds that suppress microglial overactivation.
  • Investigated the molecular pathway involving MEF2C, p21, CDK2, RB, and NFκB.
  • Assessed the efficacy of a CDK2 inhibitor (BMS265246) in vitro and in Mef2c-deficient mouse models.

Main Results:

  • MEF2C-/- iMGLs exhibited overactivation upon lipopolysaccharide stimulation.
  • BMS265246, a CDK2 inhibitor, suppressed MEF2C-/- iMGL overactivation and normalized inflammatory responses.
  • MEF2C upregulates p21, which inhibits CDK2-mediated RB degradation, preventing NFκB nuclear translocation and microglial overactivation.
  • BMS265246 treatment ameliorated microglial overactivation and ASD-like behaviors in Mef2c-deficient mice.

Conclusions:

  • The MEF2C-p21-CDK2-RB-NFκB axis is critical for maintaining microglial homeostasis.
  • CDK2 inhibition represents a promising therapeutic strategy for neuroinflammation and associated neurological disorders.
Keywords:
ASDCDK2MEF2Cimmune checkpointmicroglianeuroinflammationneurological disorders

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