ArticleActa pharmacologica Sinica2024
ABBV-744 alleviates LPS-induced neuroinflammation via regulation of BATF2-IRF4-STAT1/3/5 axis.
Article in Acta pharmacologica Sinica, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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10 citing papers in PubMed.
- Fragment-Based Discovery of BRD4-BD2 Selective Binders: Biophysical Validation and Structural Insights for Domain-Selective Inhibitor Design.ACS omega · 2026Article
- Development of cell-active BRD4-D1 selective inhibitors to decode the role of BET proteins in LPS-mediated liver inflammation.European journal of medicinal chemistry · 2026Article
- Interferon regulatory factor 4 as a context-dependent regulator of inflammation: transcriptional and epigenetic control, skin diseases, and translational challenges.Frontiers in immunology · 2026Review
- Single-cell transcriptomics reveals distinct microglial state remodeling associated with the (R)-nicotine/diosmetin combination and galantamine in LPS-challenged BV2 cells.Frontiers in immunology · 2026Article
- Steroid Receptor Coactivator-1 Drives Tumor-Associated Macrophage Reprogramming by Mediating MMP12 Transcription in Pancreatic Cancer Perineural Invasion.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Identification of BET inhibitors (BETi) against solitary fibrous tumor (SFT) through high-throughput screening (HTS).Neoplasia (New York, N.Y.) · 2025Article
- Enhancer Profiling Reveals a Protective Role of RXRα Against Calcium Oxalate-Induced Crystal Deposition and Kidney Injury.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- STAT1 mediates the pro-inflammatory role of GBP5 in colitis.Communications biology · 2025Article
- p65 enhanced METTL3-mediated mCentral-European journal of immunology · 2025Article
- Design, synthesis, and anti-inflammatory activity of 2H-1,4-benzoxazin-3(4H)-one derivatives modified with 1,2,3-triazole in LPS-induced BV-2 cells.Frontiers in pharmacology · 2024Article
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7 authors.
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Abstract
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.
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