Frontiers in bioscience (Landmark edition) · 2025
Notch1 Inhibition Exacerbates APAP-Induced Liver Injury via β-Catenin and Macrophage Polarization.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Yang Tao, Dai Jingjing, Zhou Junlan, Shao Yuyun, Wang Xiao, Zhao Jiaying, Li Jun, Shi Ping, Jiang Longfeng
Аннотация
BACKGROUND: Notch1 signaling regulates innate immune-mediated inflammation in acute liver injury (ALI). However, the precise mechanism by which Notch1 governs macrophage polarization during ALI remains poorly understood.
METHODS: Wild-type (WT) mice received DAPT (10 mg/kg) prior to acetaminophen (APAP)-induced ALI. In parallel, bone marrow-derived macrophages (BMMs) were pretreated with either the β-catenin inhibitor XAV939 or the activator SKL2001, exposed to DAPT, and then challenged with lipopolysaccharide (LPS). Liver injury and inflammation were evaluated by hematoxylin and eosin (H&E) staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunohistochemistry, immunofluorescence, quantitative real-time PCR (RT-PCR), and western blotting.
RESULTS: Unexpectedly, DAPT treatment exacerbated APAP-induced liver injury (AILI), resulting in more severe hepatocellular damage and inflammation than in controls. DAPT-treated macrophages exhibited enhanced pro-inflammatory cytokines expression and a shift toward an M1-like phenotype. Mechanistically, the β-catenin/glycogen synthase kinase 3 beta (GSK3β) signaling pathway emerged as a pivotal regulator of macrophage polarization.
CONCLUSIONS: Notch1 inhibition unexpectedly worsens AILI by amplifying macrophage-driven pro-inflammatory responses via β-catenin signaling. These findings highlight the Notch1-β-catenin axis as a key regulator of hepatic macrophage function and a potential therapeutic target for sterile liver inflammation.
METHODS: Wild-type (WT) mice received DAPT (10 mg/kg) prior to acetaminophen (APAP)-induced ALI. In parallel, bone marrow-derived macrophages (BMMs) were pretreated with either the β-catenin inhibitor XAV939 or the activator SKL2001, exposed to DAPT, and then challenged with lipopolysaccharide (LPS). Liver injury and inflammation were evaluated by hematoxylin and eosin (H&E) staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunohistochemistry, immunofluorescence, quantitative real-time PCR (RT-PCR), and western blotting.
RESULTS: Unexpectedly, DAPT treatment exacerbated APAP-induced liver injury (AILI), resulting in more severe hepatocellular damage and inflammation than in controls. DAPT-treated macrophages exhibited enhanced pro-inflammatory cytokines expression and a shift toward an M1-like phenotype. Mechanistically, the β-catenin/glycogen synthase kinase 3 beta (GSK3β) signaling pathway emerged as a pivotal regulator of macrophage polarization.
CONCLUSIONS: Notch1 inhibition unexpectedly worsens AILI by amplifying macrophage-driven pro-inflammatory responses via β-catenin signaling. These findings highlight the Notch1-β-catenin axis as a key regulator of hepatic macrophage function and a potential therapeutic target for sterile liver inflammation.