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

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 poorly 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 based on ATAC-sequencing reveals downregulation of GATA3 and PU.1, key transcription factors in T _H 2 and T _H 9 differentiation, and upregulation of REV-ERB, an antagonist of T _H 17 differentiation. By in parallel examining T cell responses to oleic acid, a monounsaturated fatty acid, and palmitic acid, a saturated fatty acid, we find that both the intensity of the transcriptomic response and the involvement of anti-inflammatory pathways is highly specific for EPA. Thus, EPA can induce an anti-inflammatory transcriptomic landscape in CD4 ⁺ T cells, a process that may contribute to the unexpectedly strong beneficial effects of EPA on the risk of atherosclerotic cardiovascular disease in clinical trials.