The Set7 Lysine Methyltransferase Regulates Plasticity in Oxidative Phosphorylation Necessary for Trained Immunity Induced by β-Glucan
The Set7 Lysine Methyltransferase Regulates Plasticity in Oxidative Phosphorylation Necessary for Trained Immunity Induced by β-Glucan
复制标题
DOI：
10.1016/j.celrep.2020.107548
复制
发表时间：
2020-04-21
期刊：
影响因子：
8.8
通讯作者：
Riksen, Niels P.
中科院分区：
文献类型：
--
作者：
Keating, Samuel T.;Groh, Laszlo;Riksen, Niels P.
经过训练的免疫通过依赖于代谢和转录重编程的过程，赋予先天免疫细胞对继发性挑战的持续增强反应。由于其先前与代谢和转录记忆的关联，以及H3组蛋白赖氨酸4单甲基化（H3K4me1）对先天免疫记忆的重要性，我们假设Set7甲基转移酶在β -葡聚糖诱导的训练免疫中起重要作用。通过对人原代单核细胞的药理学研究，我们确定了Set7调节的训练免疫特异性免疫代谢途径，包括以前未报道的诱导氧化磷酸化的h3k4me1依赖性可塑性。体内β -葡聚糖训练的重述进一步确定了set7依赖性基因表达的变化，这些变化先前与训练免疫中骨髓生成祖细胞的调节有关。通过揭示Set7作为训练免疫的关键调节因子，这些发现为持续的元代谢变化提供了机制见解，并强调了表征先天免疫记忆调节回路的重要性。
Trained immunity confers a sustained augmented response of innate immune cells to a secondary challenge, via a process dependent on metabolic and transcriptional reprogramming. Because of its previous associations with metabolic and transcriptional memory, as well as the importance of H3 histone lysine 4 monomethylation (H3K4me1) to innate immune memory, we hypothesize that the Set7 methyltransferase has an important role in trained immunity induced by beta-glucan. Using pharmacological studies of human primary monocytes, we identify trained immunity-specific immunometabolic pathways regulated by Set7, including a previously unreported H3K4me1-dependent plasticity in the induction of oxidative phosphorylation. Recapitulation of beta-glucan training in vivo additionally identifies Set7-dependent changes in gene expression previously associated with the modulation of myelopoiesis progenitors in trained immunity. By revealing Set7 as a key regulator of trained immunity, these findings provide mechanistic insight into sustained meta- bolic changes and underscore the importance of characterizing regulatory circuits of innate immune memory.