Ziogas Athanasios, Novakovic Boris, Ventriglia Lorenzo, Galang Noriko, Tran Kim A, Li Wenchao, Matzaraki Vasiliki, van Unen Nienke, Schlüter Titus, Ferreira Anaísa V, Moorlag Simone J C F M, Koeken Valerie A C M, Moyo Mthabisi, Li Xiaolin, Baltissen Marijke P A, Martens Joost H A, Li Yang, Divangahi Maziar, Joosten Leo A B, Mhlanga Musa M, Netea Mihai G
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Cell Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, the Netherlands.
Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Australia.
Cell. 2025 Apr 25. doi: 10.1016/j.cell.2025.03.048.
Trained immunity, a de facto innate immune memory characterized by enhanced responsiveness to future challenges, is underpinned by epigenetic and metabolic rewiring. In individuals vaccinated with Bacille Calmette-Guérin (BCG), lactate release was associated with enhanced cytokine responsiveness upon restimulation. Trained monocytes/macrophages are characterized by lactylation of histone H3 at lysine residue 18(H3K18la), mainly at distal regulatory regions. Histone lactylation was positively associated with active chromatin and gene transcription, persisted after the elimination of the training stimulus, and was strongly associated with "trained" gene transcription in response to a secondary stimulus. Increased lactate production upon induction of trained immunity led to enhanced production of proinflammatory cytokines, a process associated with histone lactylation. Pharmacological inhibition of lactate production or histone lactylation blocked trained immunity responses, while polymorphisms of LDHA and EP300 genes modulated trained immunity. Long-term histone lactylation persisted in vivo 90 days after vaccination with BCG, highlighting H3K18la as an epigenetic mark of innate immune memory.
训练有素的免疫是一种事实上的先天性免疫记忆，其特征是对未来挑战的反应性增强，它由表观遗传和代谢重编程所支撑。在接种卡介苗（BCG）的个体中，乳酸释放与再次刺激时细胞因子反应性增强有关。受过训练的单核细胞/巨噬细胞的特征是组蛋白H3在赖氨酸残基18（H3K18la）处发生乳酰化，主要发生在远端调控区域。组蛋白乳酰化与活跃染色质和基因转录呈正相关，在消除训练刺激后仍持续存在，并且与对二次刺激的“训练有素”的基因转录密切相关。诱导训练有素的免疫时乳酸产量增加导致促炎细胞因子产生增加，这一过程与组蛋白乳酰化有关。对乳酸产生或组蛋白乳酰化的药理学抑制会阻断训练有素的免疫反应，而LDHA和EP300基因的多态性会调节训练有素的免疫。接种卡介苗90天后，长期的组蛋白乳酰化在体内持续存在，突出了H3K18la作为先天性免疫记忆的表观遗传标记。
