当前位置: X-MOL 学术Acta Pharmacol. Sin. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
ABBV-744 alleviates LPS-induced neuroinflammation via regulation of BATF2-IRF4-STAT1/3/5 axis
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2024-06-11 , DOI: 10.1038/s41401-024-01318-4
Le-le Wang , Huan Wang , Si-jin Lin , Xing-yu Xu , Wen-juan Hu , Jia Liu , Hai-yan Zhang

Suppression of neuroinflammation using small molecule compounds targeting the key pathways in microglial inflammation has attracted great interest. Recently, increasing attention has been gained to the role of the second bromodomain (BD2) of the bromodomain and extra-terminal (BET) proteins, while its effect and molecular mechanism on microglial inflammation has not yet been explored. In this study, we evaluated the therapeutic effects of ABBV-744, a BD2 high selective BET inhibitor, on lipopolysaccharide (LPS)-induced microglial inflammation in vitro and in vivo, and explored the key pathways by which ABBV-744 regulated microglia-mediated neuroinflammation. We found that pretreatment of ABBV-744 concentration-dependently inhibited the expression of LPS-induced inflammatory mediators/enzymes including NO, TNF-α, IL-1β, IL-6, iNOS, and COX-2 in BV-2 microglial cells. These effects were validated in LPS-treated primary microglial cells. Furthermore, we observed that administration of ABBV-744 significantly alleviated LPS-induced activation of microglia and transcriptional levels of pro-inflammatory factors TNF-α and IL-1β in mouse hippocampus and cortex. RNA-Sequencing (RNA-seq) analysis revealed that ABBV-744 induced 508 differentially expressed genes (DEGs) in LPS-stimulated BV-2 cells, and gene enrichment and gene expression network analysis verified its regulation on activated microglial genes and inflammatory pathways. We demonstrated that pretreatment of ABBV-744 significantly reduced the expression levels of basic leucine zipper ATF-like transcription factor 2 (BATF2) and interferon regulatory factor 4 (IRF4), and suppressed JAK-STAT signaling pathway in LPS-stimulated BV-2 cells and mice, suggesting that the anti-neuroinflammatory effect of ABBV-744 might be associated with regulation of BATF2-IRF4-STAT1/3/5 pathway, which was confirmed by gene knockdown experiments. This study demonstrates the effect of a BD2 high selective BET inhibitor, ABBV-744, against microglial inflammation, and reveals a BATF2-IRF4-STAT1/3/5 pathway in regulation of microglial inflammation, which might provide new clues for discovery of effective therapeutic strategy against neuroinflammation.



中文翻译:


ABBV-744 通过调节 BATF2-IRF4-STAT1/3/5 轴减轻 LPS 诱导的神经炎症



使用针对小胶质细胞炎症关键通路的小分子化合物抑制神经炎症引起了极大的兴趣。近年来,人们越来越关注溴结构域和外末端 (BET) 蛋白的第二溴结构域 (BD2) 的作用,而其对小胶质细胞炎症的影响和分子机制尚未得到探索。在这项研究中,我们评估了 BD2 高选择性 BET 抑制剂 ABBV-744 对脂多糖 (LPS) 诱导的小胶质细胞炎症的体外和体内治疗效果,并探讨了 ABBV-744 调节小胶质细胞介导的神经炎症的关键途径。我们发现 ABBV-744 浓度预处理依赖于性地抑制 LPS 诱导的炎症介质/酶的表达,包括 NO 、 TNF-α、 IL-1β 、 IL-6 、 iNOS 和 COX-2 在 BV-2 小胶质细胞中。这些效果在 LPS 处理的原代小胶质细胞中得到了验证。此外,我们观察到 ABBV-744 的给药显着减轻了 LPS 诱导的小胶质细胞激活以及小鼠海马和皮层中促炎因子 TNF-α 和 IL-1β 的转录水平。RNA-测序 (RNA-seq) 分析显示,ABBV-744 在 LPS 刺激的 BV-2 细胞中诱导了 508 个差异表达基因 (DEGs),基因富集和基因表达网络分析验证了其对活化的小胶质细胞基因和炎症通路的调节。 我们证明 ABBV-744 预处理显著降低 LPS 刺激的 BV-2 细胞和小鼠中碱性亮氨酸拉链 ATF 样转录因子 2 (BATF2) 和干扰素调节因子 4 (IRF4) 的表达水平,并抑制 JAK-STAT 信号通路,提示 ABBV-744 的抗神经炎症作用可能与 BATF2-IRF4-STAT1/3/5 通路的调节有关,基因敲低实验证实了这一点。本研究证明了 BD2 高选择性 BET 抑制剂 ABBV-744 对小胶质细胞炎症的作用,并揭示了 BATF2-IRF4-STAT1/3/5 通路在调节小胶质细胞炎症方面的作用,这可能为发现针对神经炎症的有效治疗策略提供新的线索。

更新日期:2024-06-11
down
wechat
bug