ABBV-744 alleviates LPS-induced neuroinflammation via regulation of BATF2-IRF4-STAT1/3/5 axis
文献类型：期刊论文
| 作者 | Wang, Le-le2,3; Wang, Huan2,3; Lin, Si-jin2,3; Xu, Xing-yu2,3; Hu, Wen-juan1 ; Liu, Jia1; Zhang, Hai-yan2,3
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2024-06-11 |
| 页码 | 15 |
| 关键词 | microglial inflammation BD2 ABBV-744 BATF2 IRF4 JAK/STAT |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/s41401-024-01318-4 |
| 通讯作者 | Zhang, Hai-yan(hzhang@simm.ac.cn) |
| 英文摘要 | 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-alpha, IL-1 beta, 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-alpha and IL-1 beta 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. |
| WOS关键词 | MOUSE MODEL ; TRANSCRIPTIONAL REGULATORS ; MICROGLIA ; ACTIVATION ; INHIBITOR ; RESPONSES ; IMMUNE ; INFLAMMATION ; MECHANISMS ; DISEASES |
| 资助项目 | Innovation of Science and Technology[2021ZD0200900] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001243864800002 |
| 出版者 | NATURE PUBL GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/311573]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhang, Hai-yan |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Le-le,Wang, Huan,Lin, Si-jin,et al. ABBV-744 alleviates LPS-induced neuroinflammation via regulation of BATF2-IRF4-STAT1/3/5 axis[J]. ACTA PHARMACOLOGICA SINICA,2024:15. |
| APA | Wang, Le-le.,Wang, Huan.,Lin, Si-jin.,Xu, Xing-yu.,Hu, Wen-juan.,...&Zhang, Hai-yan.(2024).ABBV-744 alleviates LPS-induced neuroinflammation via regulation of BATF2-IRF4-STAT1/3/5 axis.ACTA PHARMACOLOGICA SINICA,15. |
| MLA | Wang, Le-le,et al."ABBV-744 alleviates LPS-induced neuroinflammation via regulation of BATF2-IRF4-STAT1/3/5 axis".ACTA PHARMACOLOGICA SINICA (2024):15. |
入库方式： OAI收割
来源：上海药物研究所
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