Aurora kinase A promotes trained immunity via regulation of endogenous S-adenosylmethionine metabolism

作者：Mengyun Li, Huan Jin, Yongxiang Liu, Zining Wang, Lin Li, Tiantian Wang, Xiaojuan Wang, Hongxia Zhang, Bitao Huo, Tiantian Yu, Shoujie Wang, Wei Zhao, Jinyun Liu, Peng Huang, Jun Cui, Xiaojun Xia · 发表于：eLife · 年份：2025 · DOI：10.7554/elife.104138.3 · 被引用次数：3 · 研究领域：Immune responses and vaccinations、Epigenetics and DNA Methylation、Neonatal Respiratory Health Research

Innate immune cells can acquire a memory phenotype, termed trained immunity, but the mechanism underlying the regulation of trained immunity remains largely elusive. Here, we demonstrate that inhibition of Aurora kinase A (AurA) dampens trained immunity induced by β-glucan. ATAC-seq and RNA-seq analysis reveal that AurA inhibition restricts chromatin accessibility of genes associated with inflammatory pathways such as JAK-STAT, TNF, and NF-κB pathways. Specifically, AurA inhibition promotes nuclear localization of FOXO3 and the expression of glycine N-methyltransferase (GNMT), a key enzyme responsible for S-adenosylmethionine (SAM) consumption. Metabolomic analysis confirms a reduction in SAM level upon AurA inhibition. As a result of SAM deficiency, trained mouse macrophages exhibit decreased H3K4me3 and H3K36me3 enrichment on gene regions of Il6 and Tnf . Additionally, the tumor inhibition effect of β-glucan is notably abolished by AurA inhibition. Together, our findings identify an essential role of AurA in regulating trained immunity via a methylation-dependent manner by maintaining endogenous SAM levels through the mTOR-FOXO3-GNMT axis.