Gan Hui, Zhang Mi, Duan Yuhao, Palahati Ailiyaer, He Qi, Tan Junyi, Li Yong, Zhai Xuan, Zhao Jing
Department of Neurosurgery Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Chongqing 400010, China.
Center for Neuroscience Research, School of Basic Medicine, Chongqing Medical University, Chongqing 400016, China.
Genes Dis. 2025 Apr 1;12(6):101614. doi: 10.1016/j.gendis.2025.101614. eCollection 2025 Nov.
Microglial activation triggers the inflammatory cascade and exacerbates brain injury following ischemic stroke. Middle cerebral artery occlusion (MCAO) modeling increased the expression of nuclear factor of activated T cells 5 (NFAT5) in microglia. However, the role of microglial NFAT5 in ischemic stroke remains unclear. Here, our findings indicated that microglial NFAT5 knockdown reduced the expression of pro-inflammatory factors, microglial activation, and neutrophil infiltration, ultimately ameliorating cerebral infarction and neurological deficits in mice following MCAO. Additionally, we treated hippocampal neuronal cells (HT22) with a conditioned culture medium from a microglia cell line (BV2) to simulate microglia-induced neuronal injury . We observed that NFAT5 knockdown attenuated the expression of pro-inflammatory factors in BV2 cells and reduced apoptosis in HT22 cells. Previously, our published work reported that the NOD-like receptor pyrin domain-containing 6 (NLRP6) inflammasome contributed to inflammatory injury after MCAO. In this study, we discovered that NFAT5 promoted the transcriptional activity of the promoter through its -1527 bp to -1518 bp element. Notably, our results also demonstrated that NFAT5 regulated the stability of NLRP6 mRNA via the 5'UTR of . Thus, our findings reveal the pivotal role and partial mechanism of microglial NFAT5 in neuroinflammation following ischemic stroke.
小胶质细胞激活会触发炎症级联反应，并加剧缺血性中风后的脑损伤。大脑中动脉闭塞（MCAO）模型增加了小胶质细胞中活化T细胞核因子5（NFAT5）的表达。然而，小胶质细胞NFAT5在缺血性中风中的作用仍不清楚。在此，我们的研究结果表明，小胶质细胞NFAT5基因敲低可降低促炎因子的表达、小胶质细胞激活和中性粒细胞浸润，最终改善MCAO后小鼠的脑梗死和神经功能缺损。此外，我们用小胶质细胞系（BV2）的条件培养基处理海马神经元细胞（HT22），以模拟小胶质细胞诱导的神经元损伤。我们观察到NFAT5基因敲低减弱了BV2细胞中促炎因子的表达，并减少了HT22细胞的凋亡。此前，我们发表的研究报道含pyrin结构域的NOD样受体6（NLRP6）炎性小体在MCAO后导致炎症损伤。在本研究中，我们发现NFAT5通过其-1527 bp至-1518 bp元件促进启动子的转录活性。值得注意的是，我们的结果还表明，NFAT5通过的5'UTR调节NLRP6 mRNA的稳定性。因此，我们的研究结果揭示了小胶质细胞NFAT5在缺血性中风后神经炎症中的关键作用和部分机制。
