代谢和先天免疫线索通过UPR合并为特定的炎症反应
Denis A Mogilenko1, Joel T Haas1, Laurent L'homme1
1University of Lille, EGID, INSERM, CHU Lille, Institut Pasteur de Lille, U1011, 59019 Lille, France.
Cell
|April 30, 2019
概括
高脂肪酸环境通过改变新陈代谢来恶化树突细胞中的托尔类受体反应. 这导致线粒体反应性氧物种和炎症增加,突出显示了新陈代谢与先天免疫之间的联系.
科学领域:
- 免疫学
- 代谢过程
- 细胞生物学
背景情况:
- 骨髓细胞的先天免疫反应与细胞内代谢密切相关.
- 托尔类受体 (TLR) 刺激促进糖解,而抗炎信号需要线粒体呼吸.
- 外部代谢信号对免疫反应的影响在很大程度上仍未被探索.
研究的目的:
- 研究外源代谢信号,特别是脂肪酸如何影响树突细胞 (DC) 中的TLR依赖免疫反应.
- 阐明脂肪酸代谢与免疫细胞激活和细胞因子产生之间的分子机制.
主要方法:
- 使用高脂肪酸 (FA) 的代谢环境来研究TLR刺激的树突细胞 (DC).
- 评估了包括糖解和三碳酸循环在内的代谢途径.
- 测量了线粒体的活性氧物种 (mtROS) 生产和未折叠的蛋白质反应 (UPR).
- 分析了转录形状和IL-23表达.
- 使用代谢途径和关键蛋白质的遗传和化学抑制 (例如,XBP1).
- 在依赖IL-23的牛皮模型中评估皮肤炎症.
主要成果:
- 高脂肪酸环境会加剧依赖TLR的直流反应.
- 脂肪酸可以抑制六酶的活性,并破坏三酸循环的代谢.
- 代谢变化增加了mtROS的产生,并触发了UPR.
- 这导致具有高IL-23产生的独特的转录基因特征.
- 抑制糖溶解模仿了这些效应.
- 减少的mtROS或XBP1缺乏减弱了IL-23的表达和皮肤炎症.
结论:
- 优化新陈代谢需求是先天免疫的关键.
- 减少mtROS诱导的UPR对于调节炎症反应至关重要.
- 脂肪酸代谢显著影响DC功能和炎症潜力,特别是通过IL-23.
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