缺血性卒中中，CEBPB-AP-1（JunB/Fos）轴通过TNF信号驱动神经炎症和小胶质细胞功能障碍
The CEBPB-AP-1 (JunB/Fos) Axis Drives Neuroinflammation and Microglial Dysfunction Via TNF Signaling in Ischemic Stroke.
摘要(中文译文)
缺血性卒中会触发强烈的神经炎症反应，其中小胶质细胞发挥双重作用，既加重组织损伤，又促进修复。调控小胶质细胞活化和极化的分子机制目前尚不明确。在本研究中，我们证明转录因子CEBPB是AP-1（JunB-Fos）复合物的关键上游调控因子，在短暂性局灶性脑缺血（tFCI）后驱动小胶质细胞的促炎转录程序。对tFCI小鼠小胶质细胞的转录组分析显示基因表达发生显著变化，尤其富集于炎症、免疫和细胞因子产生通路，并确定Cebpb、Junb、Fos和Tnf为关键枢纽基因。在机制上，CEBPB在缺血后小胶质细胞中上调，并直接结合Fos启动子以激活AP-1，诱导下游炎症介质，包括IL-1β和TNF-α。使用选择性抑制剂T-5224抑制AP-1可在体外使小胶质细胞从促炎表型转变为抗炎表型，减少促炎细胞因子产生并增强抗炎介质释放。在体内，对tFCI小鼠给予T-5224治疗可抑制神经炎症，减少纹状体和皮质中的神经元凋亡，促进修复性小胶质细胞表型，并改善长期感觉运动和认知功能。这些发现确立了CEBPB/AP-1轴作为缺血性卒中神经炎症的关键驱动因素，并突显其作为有前景的治疗靶点。
Abstract
Ischemic stroke triggers a strong neuroinflammatory response, with microglia playing dual roles in both exacerbating tissue damage and promoting repair. The molecular mechanisms regulating microglial activation and polarization remain inadequately defined. In this study, we demonstrate that the transcription factor CEBPB is a key upstream regulator of the AP-1 (JunB-Fos) complex, driving pro-inflammatory transcriptional programs in microglia following transient focal cerebral ischemia (tFCI). Transcriptomic profiling of microglia from tFCI mice revealed significant gene expression changes, particularly enrichment in inflammatory, immune, and cytokine production pathways, and identified Cebpb, Junb, Fos, and Tnf as key hub genes. Mechanistically, CEBPB is upregulated in post-ischemic microglia and directly binds to the Fos promoter to activate AP-1, inducing downstream inflammatory mediators, including IL-1β and TNF-α. Inhibition of AP-1 with the selective inhibitor T-5224 shifted microglia from a pro-inflammatory to an anti-inflammatory phenotype in vitro, decreasing pro-inflammatory cytokine production and enhancing anti-inflammatory mediator release. In vivo, T-5224 treatment in tFCI mice suppressed neuroinflammation, reduced neuronal apoptosis in the striatum and cortex, promoted a restorative microglial phenotype, and improved long-term sensorimotor and cognitive function. These findings establish the CEBPB/AP-1 axis as a critical driver of neuroinflammation in ischemic stroke and highlight it as a promising therapeutic target.
如何引用
AMA
Kun Liang, Shuangshuang Lu, Weihao Shi, Weijian Fan, Yijun Huang, Jianwei Chen, et al. The CEBPB-AP-1 (JunB/Fos) Axis Drives Neuroinflammation and Microglial Dysfunction Via TNF Signaling in Ischemic Stroke.. Inflammation. 2026; doi:10.1007/s10753-026-02525-3.
APA
Kun Liang, Shuangshuang Lu, Weihao Shi, Weijian Fan, Yijun Huang, Jianwei Chen, et al (2026). The CEBPB-AP-1 (JunB/Fos) Axis Drives Neuroinflammation and Microglial Dysfunction Via TNF Signaling in Ischemic Stroke.. Inflammation. https://doi.org/10.1007/s10753-026-02525-3
GB/T 7714
Kun Liang, Shuangshuang Lu, Weihao Shi, Weijian Fan, Yijun Huang, Jianwei Chen, et al. The CEBPB-AP-1 (JunB/Fos) Axis Drives Neuroinflammation and Microglial Dysfunction Via TNF Signaling in Ischemic Stroke.[J]. Inflammation, 2026 doi:10.1007/s10753-026-02525-3.
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