巨细胞Dvl2缺乏促进NOD1驱动的热,并加剧炎症性肝损伤
Xiaoye Qu1, Dongwei Xu1, Tao Yang2
1The Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA; Department of Liver Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Redox biology
|December 7, 2024
概括
巨异形2 (Dvl2) 缺陷通过促进NOD1介导的亡和破坏YAP-HSF1轴,使肝损伤恶化. 在巨细胞中恢复eEF2可以减轻这种损伤,突出显示Dvl2.
科学领域:
- 免疫学和分子生物学
- 肝病学和炎症性肝病研究研究
背景情况:
- Dishevelled 2 (Dvl2),一个无翼/Wnt通路调解者,影响细胞功能,但其在巨介导的肝损伤中的作用尚不清楚.
- 氧化应激和炎症引发肝损伤,涉及NOD1介导的亡和肝细胞死亡等途径.
研究的目的:
- 为了调查巨Dvl2在调节NOD1介导的热和肝细胞死亡在氧化应激诱导的肝损伤期间的作用.
- 在这个过程中阐明涉及YAP-HSF1轴和eEF2的分子机制.
主要方法:
- 使用了一种氧化应激诱导的肝炎 (缺血/反应激) 的小鼠模型.
- 采用了特定于骨髓细胞的Dvl2淘汰 (Dvl2M-KO) 和对照 (Dvl2FL/FL) 鼠标.
- 在肝脏组织和共同培养中分析了巨细胞激活标记物 (NOD1,caspase-1,GSDMD,NF-κB),YAP-HSF1相互作用和eEF2表达.
主要成果:
- Dvl2M-KO小鼠表现出恶化的肝损伤,增加的氧化应激,和高的亲炎性介质后IR压力.
- 巨细胞Dvl2缺陷增强了NOD1,酶-1,GSDMD和NF-κB的激活,同时减少了YAP-HSF1的核聚合和相互作用.
- eEF2表达抑制了NOD1/caspase-1和GSDMD激活;巨细胞eEF2删除恶化了 pyroptosis 和肝细胞死亡,这是通过eEF2表达巨细胞转移得到改善的.
结论:
- 巨细胞Dvl2缺乏会通过破坏YAP-HSF1轴,促进NOD1介导的热致死和肝细胞死亡,从而加剧肝损伤.
- eEF2在抑制NOD1驱动的热和肝损伤中的炎症反应中发挥着关键作用.
- 大细胞Dvl2和eEF2代表了器官缺血-再输液损伤和移植受体的潜在治疗点.
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