在维持肠道平衡中,TRADD和RIPK1依赖的细胞死亡途径的合作
Ziyu Sun1,2,3, Jianyu Ye1,2,3, Weimin Sun1
1Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 201203, Shanghai, China.
Nature communications
|February 22, 2025
概括
功能障碍的NF-κB信号驱动着炎症性肠病 (IBD). 针对RIPK1和TRADD一起提供了一种有前途的IBD新疗法,通过预防肠道病理和致命性来预防IBD.
科学领域:
- 免疫学 免疫学 免疫学
- 胃肠病学 胃肠病学
- 分子生物学分子生物学
背景情况:
- 功能障碍的核因子-kappa B (NF-κB) 信号传递是炎症性肠病 (IBD) 病原体的核心.
- 受体相互作用蛋白激酶1 (RIPK1) 和TNF受体相关因子2 (TRADD) 是NF-κB通路中的关键调解者.
研究的目的:
- 阐明RIPK1和TRADD在IBD病变发生过程中的机制性作用.
- 在IBD的小鼠模型中研究准RIPK1和TRADD的治疗潜力.
主要方法:
- 使用了一种缺乏肠上皮细胞 (IEC) 转化生长因子激活激酶1 (TAK1) 的小鼠模型.
- 分析了TAK1对TRADD的酸化及其对RIPK1依赖性亡的影响.
- 评估TRADD和RIPK1在TNF和托尔类受体 (TLR) 信号介导细胞死亡中的合作作用.
- 研究了从RIPK1-依赖性结肠炎到RIPK1-和TRADD-共依赖性结肠炎的病态进展.
- 评估了联合RIPK1抑制和TRADD淘汰在防止肠道病理和致死性的有效性.
- 鉴定了与不同疾病表型相关的微生物群失生症生物标志物.
主要成果:
- TAK1缺乏导致TRADD酸化,调节RIPK1依赖的亡.
- RIPK1和TRADD合作调解TNF和TLR信号的下游细胞死亡.
- 在TAK1 IEC缺陷小鼠中观察到从RIPK1-依赖性结肠炎到RIPK1-和TRADD-共依赖性结肠炎的病理演变.
- 结合RIPK1抑制和TRADD淘汰作用,完全防止肠道病理和致死性.
- 针对RIPK1-依赖性乳头炎和TRADD-依赖性结肠炎,已经确定了显著的微生物群失调生物标志物.
结论:
- RIPK1和TRADD合作调解NF-κB缺乏IBD的细胞死亡和炎症.
- 联合抑制RIPK1激酶和TRADD代表了IBD的潜在新疗法策略.
- 微生物群失生症作为RIPK1和TRADD驱动的特定IBD病理的生物标志物.
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