Eicosapentaenoic acid induces an anti-inflammatory transcriptomic landscape in T cells implicating a pathway independent of triglyceride lowering in cardiovascular risk reduction [ATAC-seq]

A twice-daily dose of highly purified eicosapentaenoic acid (EPA) reduces the risk of atherosclerotic cardiovascular disease among patients with high triglycerides and either known cardiovascular disease or those at high risk for developing it. However, the process by which EPA exerts its beneficial effects remains ill understood. Here, we show that EPA can induce an anti-inflammatory transcriptional profile in non-activated CD4+ T cells. We find that EPA exposed CD4+ T cells downregulate immune response related genes, such as HLA-DRA, CD69, and IL2RA, while upregulating genes involved in oxidative stress prevention, such as NQO1. Furthermore, transcription footprint analysis reveals downregulation of GATA3 and PU.1, key transcription factors in TH2 and TH9 differentiation, and upregulation of REV-ERB, an antagonist of TH17 differentiation. Additionally, we examine T cell responses to two other fatty acids of varying degrees of saturation, namely oleic and palmitic acid, and find EPA has a distinct effect on CD4+ T cells transcriptomic landscape as compared to control. Thus, our study shows that EPA can already induce beneficial transcriptomic profiles in CD4+ T cells prior to activation, a process that may contribute to the unexpectedly strong beneficial effects of EPA on atherosclerotic cardiovascular disease observed in clinical trials.