The transcription factor MEF2C restrains microglial overactivation by inhibiting kinase CDK2

  • Immunity. 2025 Apr 8;58(4):946-960.e10. doi: 10.1016/j.immuni.2025.02.026.
Xiaodan Hu  1 ,  Jianchen Wu  1 ,  Lu Shi  2 ,  Folin Wang  1 ,  Kezhang He  1 ,  Pengcheng Tan  1 ,  Yanyan Hu  1 ,  Yuanyuan Yang  1 ,  Dan Wang  1 ,  Tianhua Ma  3 ,  Sheng Ding  4
Affiliations
  • 1. New Cornerstone Science Laboratory, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
  • 2. CRE Life Institute, Beijing 100000, China.
  • 3. New Cornerstone Science Laboratory, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China. Electronic address: [email protected].
  • 4. New Cornerstone Science Laboratory, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address: [email protected].
PMID: 40139186 DOI: 10.1016/j.immuni.2025.02.026
Abstract

Microglial intrinsic immune checkpoints are essential safeguards to maintain immune homeostasis by preventing microglial overactivation, a process that substantially influences neurological disorders such as autism spectrum disorder (ASD). MEF2C is a crucial immune checkpoint that regulates microglial activation, but the mechanism remains unclear. We found that MEF2C-deficient (MEF2C-/-) induced microglia-like cells (iMGLs) derived from human pluripotent stem cells (hPSCs) exhibited overactivation following lipopolysaccharide stimulation, mimicking patterns observed in various neuroinflammatory disorders. High-throughput screening identified BMS265246, a cyclin-dependent kinase 2 (CDK2) inhibitor, which suppressed overactivation of MEF2C-/- iMGLs and normalized their inflammatory responses. Mechanistically, MEF2C transcriptionally upregulated p21 to inhibit CDK2 activation-mediated retinoblastoma protein (RB) degradation, thereby preventing transcription factor nuclear factor κB (NFκB) nuclear translocation and consequent microglial overactivation. BMS265246 treatment substantially ameliorated microglial overactivation and ASD-like behaviors in Mef2c-deficient mice. Our findings identify the MEF2C-p21-CDK2-RB-NFκB axis as a critical pathway to maintain microglial homeostasis and highlight CDK2 as a potential therapeutic target for neuroinflammation.

Keywords
ASD; CDK2; MEF2C; immune checkpoint; microglia; neuroinflammation; neurological disorders.
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