The transcription factor MEF2C restrains microglial overactivation by inhibiting kinase CDK2

IF 25.5 1区医学 Q1 IMMUNOLOGY

Immunity Pub Date : 2025-03-25 DOI:10.1016/j.immuni.2025.02.026

Xiaodan Hu, Jianchen Wu, Lu Shi, Folin Wang, Kezhang He, Pengcheng Tan, Yanyan Hu, Yuanyuan Yang, Dan Wang, Tianhua Ma, Sheng Ding

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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.

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转录因子MEF2C通过抑制激酶CDK2抑制小胶质细胞过度激活

小胶质细胞固有免疫检查点是通过防止小胶质细胞过度激活来维持免疫稳态的必要保障，这一过程实质上影响着自闭症谱系障碍（ASD）等神经系统疾病。MEF2C是调节小胶质细胞激活的关键免疫检查点，但其机制尚不清楚。我们发现MEF2C缺陷（MEF2C−/−）诱导的来自人多能干细胞（hPSCs）的小胶质样细胞（iMGLs）在脂多糖刺激后表现出过度激活，模仿各种神经炎症疾病中观察到的模式。高通量筛选鉴定出周期蛋白依赖性激酶2 （CDK2）抑制剂BMS265246，该抑制剂抑制MEF2C−/−iMGLs的过度激活并使其炎症反应正常。从机制上讲，MEF2C通过转录上调p21抑制CDK2激活介导的视网膜母细胞瘤蛋白（RB）降解，从而阻止转录因子核因子κB （NFκB）核易位和随之而来的小胶质细胞过度活化。BMS265246治疗显著改善了mef2c缺陷小鼠的小胶质细胞过度激活和asd样行为。我们的研究结果确定了MEF2C-p21-CDK2-RB-NFκB轴是维持小胶质细胞稳态的关键途径，并强调了CDK2作为神经炎症的潜在治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Immunity 医学-免疫学

CiteScore

49.40

自引率

2.20%

发文量

205

审稿时长

6 months

期刊介绍： Immunity is a publication that focuses on publishing significant advancements in research related to immunology. We encourage the submission of studies that offer groundbreaking immunological discoveries, whether at the molecular, cellular, or whole organism level. Topics of interest encompass a wide range, such as cancer, infectious diseases, neuroimmunology, autoimmune diseases, allergies, mucosal immunity, metabolic diseases, and homeostasis.