一种功能丧失的人类ADAR变种激活了先天免疫反应,并促进了肠道炎症
Pengfei Xu1,2,3, Yue Xi4, Jong-Won Kim4,5,6
1Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA. pex9@pitt.edu.
Nature communications
|September 29, 2025
概括
减少RNA编辑酶ADAR (作用于RNA1的腺氨酸脱氨酶) 的表达,有助于炎症性肠病 (IBD). ADAR缺乏导致免疫系统激活,这表明ADAR-dsRNA/ERVs-MDA5-JAK/STAT轴作为IBD的治疗点.
科学领域:
- 胃肠道学和免疫学
- 在RNA生物学,RNA生物学.
- 分子医学是分子医学.
背景情况:
- 炎症性肠病 (IBD) 涉及复杂的遗传和环境因素.
- 作用于RNA 1 (ADAR) 的腺氨酸脱氨酶对于维持组织平衡至关重要.
- 在IBD患者的肠道密室中观察到ADAR表达的减少.
研究的目的:
- 为了研究ADAR在IBD病原发生中的作用.
- 阐明将ADAR缺乏与肠道炎症联系起来的分子机制.
- 为了确定IBD的潜在治疗点.
主要方法:
- 对人类IBD患者组织中ADAR表达的分析.
- 在小鼠模型中诱导ADAR缺乏,以研究大肠炎和大肠炎.
- 有机体研究,以评估ADAR损失对肠道平衡的影响.
- 编辑组分析以确定ADAR目标.
- 使用JAK1/2抑制剂Ruxolitinib的药理抑制.
主要成果:
- 人和小鼠的肠道ADAR缺乏导致IBD.
- ADAR损失导致双链RNA (dsRNA) 和内源逆转录病毒 (ERV) 的积累.
- 这种积累激活了MDA5介导的dsRNA传感和JAK/STAT信号.
- 编辑的Mda5显示dsrna感应受损,功能丧失的ADAR突变加剧IBD.
- 在小鼠模型中,ruxolitinib治疗减弱了IBD.
结论:
- ADAR-dsRNA/ERVs-MDA5-JAK/STAT信号轴与IBD病变发生有关.
- 针对这个轴,例如使用JAK抑制剂,可能为IBD提供治疗策略.
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