氨酸2A受体依赖AMPK的激活抑制TH17细胞通过表观遗传和代谢重编程的致病性
Gina Papadopoulou1,2, Dimitrios Valakos3, Ioanna Polydouri3
1Cellular Immunology Laboratory, Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece.
活性蛋白A通过增强氧化化 (OXPHOS) 通过腺A2A受体 (A2AR) -AMP激活蛋白激酶 (AMPK) 信号传递促进非致病性T辅助17 (TH17) 细胞,抑制TH17的致病性.
科学领域:
- 免疫学 免疫学 免疫学
- 代谢途径 代谢途径
- 细胞代谢的细胞代谢.
背景情况:
- 辅助性T17 (TH17) 细胞在宿主防御和自身免疫中起着至关重要的作用.
- 代谢重编程是TH17细胞功能和致病性的关键决定因素.
- 活性蛋白A是一种细胞因子,可以诱导非致病性TH17细胞分化.
研究的目的:
- 为了研究底层的代谢机制激素A介导的TH17细胞非致病性.
- 确定控制TH17细胞代谢重编程和致病性的信号通路.
主要方法:
- 在体外分化原始T细胞成TH17细胞,有或没有Activin A.
- 细胞代谢的分析,包括有氧糖解和氧化酸化 (OXPHOS).
- 研究涉及腺A2A受体 (A2AR) 和AMP激活蛋白激酶 (AMPK) 的信号通路.
- 在多发性硬化症的小鼠模型中评估TH17细胞的致病性.
- 染色体免疫沉试验分析质子修饰 (H3K9ac).
主要成果:
- 用Activin A治疗的TH17细胞表现出有氧糖解减少和OXPHOS增加.
- 通过A2AR和AMPK进行信号,增强了OXPHOS并将致病性TH17细胞重新编程到非致病性状态.
- 在致病性TH17细胞中,PCAF介导的H3K9ac向了参与有氧糖解的基因.
- 在非致病性TH17细胞中,AMPK信号抑制了PCAF介导的H3K9ac在糖溶性基因上,并在与OXPHOS相关的基因上增强了它.
- 在小鼠中,由激素A诱导的非致病性TH17细胞不会引起中枢神经系统自身免疫.
结论:
- A2AR-AMPK信号传导作为一种代谢检查点,控制TH17细胞的致病性.
- 通过A2AR-AMPK信号介导的activin A对TH17细胞进行代谢重编程,抑制了病原性.
- 准A2AR-AMPK信号可能为TH17细胞介导的自身免疫疾病提供治疗策略.
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