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

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 ß-glucan. ATAC-seq and RNA-seq analysis reveals that AurA inhibition restricts chromatin accessibility of genes associated with inflammatory pathways such as JAK-STAT, TNF and NF-?B pathways. Specifically, AurA inhibition promotes nuclear localization of FOXO3 and the expression of glycine N-methyltransferase (GNMT), a key enzyme responsible for 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 Tnfa. Additionally, the tumor inhibition effect of ß-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 level through mTOR-FOXO3-GNMT axis Overall design: Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) in trained BMDMs