氨基酸传感器GCN2通过抑制炎酶激活来控制肠道炎症
Rajesh Ravindran1, Jens Loebbermann1, Helder I Nakaya2
1Emory Vaccine Center, Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, GA 30329, USA.
Nature
|March 17, 2016
概括
一般控制的非抑制 (GCN2) 激酶感知氨基酸饥饿,通过抑制炎症酶激活来控制肠道炎症. 通过减少自,增加ROS和IL-1β产生,GCN2缺乏会增加炎症.
科学领域:
- 免疫学
- 细胞生物学
- 胃肠病学
背景情况:
- 综合应激反应 (ISR) 对细胞平衡至关重要,GCN2激酶调解对氨基酸饥饿的反应.
- 在肠道炎症中ISR和GCN2的作用尚不完全理解.
研究的目的:
- 研究GCN2在调节肠道炎症中的作用.
- 阐明GCN2控制炎细胞激活和T辅助细胞反应的分子机制.
主要方法:
- 使用了Gcn2淘汰赛小鼠模型 (CD11c-Cre Gcn2和Villin-Cre Gcn2).
- 在肠道细胞中评估了炎酶激活,IL-1β产生,自标志物 (ATG5,ATG7) 和活性氧物种 (ROS).
- 在体内使用,阻断ROS和IL-1β.
主要成果:
- 在肠道APC或上皮细胞中Gcn2缺失加剧了肠道炎症和TH17反应.
- 这种恶化与增强的炎细胞激活,IL- 1β产生,自减少和ROS增加有关.
- 阻断ROS和IL-1β可以改善Gcn2的炎症.
- 急性氨基酸饥饿抑制了依赖GCN2的方式的肠道炎症.
结论:
- 通过抑制炎症酶激活,GCN2起到关键的肠炎抑制作用.
- 通过自,ROS和IL-1β的调节,GCN2-ISR途径将氨基酸感应与肠道免疫控制相结合.
- 针对GCN2或其下游效应器可能为炎症性肠道疾病提供治疗策略.
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