ISG15在骨髓状细胞中协调了线粒体脂肪氧化和1型干扰素之间的动态交叉声
bioRxiv : the preprint server for biology
|February 26, 2026
概括
1型干扰素 (IFN) 最初促进免疫反应的脂肪酸氧化 (FAO),但后来通过ISG15.抑制它. 这种反循环调节炎症并维持免疫平衡.
科学领域:
- 免疫代谢过程中的免疫代谢.
- 细胞的新陈代谢
- 分子免疫学分子免疫学
背景情况:
- 线粒体脂肪酸氧化 (FAO) 在免疫代谢中的作用尚未完全理解,与克雷布斯循环中间体不同.
- 1型干扰素 (IFN) 信号传递对免疫反应至关重要,但其代谢调节是复杂的.
研究的目的:
- 调查线粒体脂肪酸氧化 (FAO) 在1型干扰素 (IFN) 反应中的作用.
- 阐明在免疫激活期间控制FAO的调控机制和反循环.
主要方法:
- 使用了主要骨髓衍生的巨细胞 (BMDMs) 和小鼠模型.
- 评估了粮农组织,酶活性 (CPT1a,ACAT1) 和基因素乙化.
- 采用了基因淘汰 (Isg15) 和病毒感染模型 (LCMV).
- 进行了共免疫沉,并分析了SLE患者的样本.
主要成果:
- 在BMDM中,IFN-β和STING激活增加了FAO和相关酶 (CPT1a,ACAT1).
- Cpt1a的耗尽减少了FAO和减弱了1型IFN信号,表明FAO的表观遗传作用.
- 增加的IFN反应抑制了FAO,与FAO酶的干扰素刺激基因15 (ISG15) 表达和ISGylation的增加相关.
- ISG15缺陷增强了粮农组织和1型IFN反应;ISG15与CPT1a/ACAT1.1相互作用.
- 在SLE患者中观察到ISG15升高和FAO降低.
结论:
- 1型IFN对FAO表现出双相效应:最初通过ISG15依赖的负反循环增强它,然后通过ISG15依赖的负反循环抑制它.
- 这种调节程序抑制炎症并维持免疫平衡.
- 确定了一种新的ISG15介导的调控机制,控制粮农组织在免疫反应中的作用.
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