Keating Samuel T, Groh Laszlo, van der Heijden Charlotte D C C, Rodriguez Hanah, Dos Santos Jéssica C, Fanucchi Stephanie, Okabe Jun, Kaipananickal Harikrishnan, van Puffelen Jelmer H, Helder Leonie, Noz Marlies P, Matzaraki Vasiliki, Li Yang, de Bree L Charlotte J, Koeken Valerie A C M, Moorlag Simone J C F M, Mourits Vera P, Domínguez-Andrés Jorge, Oosting Marije, Bulthuis Elianne P, Koopman Werner J H, Mhlanga Musa, El-Osta Assam, Joosten Leo A B, Netea Mihai G, Riksen Niels P
Department of Internal Medicine and Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, the Netherlands.
Epigenetics in Human Health and Disease, Department of Diabetes, Monash University, Melbourne, VIC, Australia.
Cell Rep. 2020 Apr 21;31(3):107548. doi: 10.1016/j.celrep.2020.107548.
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 β-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 β-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 metabolic changes and underscore the importance of characterizing regulatory circuits of innate immune memory.
训练有素的免疫通过一个依赖于代谢和转录重编程的过程，赋予先天免疫细胞对二次刺激的持续增强反应。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，我们推测Set7甲基转移酶在β-葡聚糖诱导的训练有素的免疫中起重要作用。通过对人类原代单核细胞的药理学研究，我们确定了由Set7调节的训练有素的免疫特异性免疫代谢途径，包括氧化磷酸化诱导中以前未报道的H3K4me1依赖性可塑性。体内β-葡聚糖训练的重现还确定了Set7依赖性基因表达变化，这些变化以前与训练有素的免疫中骨髓生成祖细胞的调节有关。通过揭示Set7是训练有素的免疫的关键调节因子，这些发现为持续的代谢变化提供了机制性见解，并强调了表征先天免疫记忆调节回路的重要性。
