Biology subjects

Hoeksema, M. A.

Publications and source records attributed to Hoeksema, M. A..

3 recordsLinked to original sources

bioRxiv2024

EPA induces an anti-inflammatory transcriptomic landscape in T cells implicating a pathway independent of triglyceride lowering in CVD 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 TH2 and TH9 differentiation, and upregulation of REV-ERB, an antagonist of TH17 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.

genomics↗

bioRxiv2024

Oleic acid triggers CD4+ T cells to be metabolically rewired and poised to differentiate into proinflammatory T cell subsets upon activation

T cells are the most common immune cells in atherosclerotic plaques and the function of T cells can be altered by fatty acids. Here, we show that pre-exposure of CD4+ T cells to oleic acid, an abundant fatty acid linked to cardiovascular events, results in a preferential differentiation into pro-inflammatory subsets upon activation by upregulating core metabolic pathways. RNA-sequencing of non-activated CD4+ T cells revealed that oleic acid upregulates genes encoding enzymes responsible for cholesterol and fatty acid biosynthesis. Transcription footprint analysis linked this rewiring to the differentiation of pro-inflammatory subsets. Indeed, spectral flow cytometry showed that pre-exposure to oleic acid results in a skew toward IL-9, IL-17A, IL-5 and IL-13 producing T cells upon activation. Importantly, inhibition of either cholesterol or fatty acid biosynthesis abolishes this effect, suggesting a beneficial role for statins beyond cholesterol lowering. Taken together, fatty acids may affect inflammatory diseases by influencing T cell metabolism.

genomics↗

bioRxiv2020

Mechanisms underlying divergent responses of genetically distinct macrophages to IL-4

Mechanisms by which non-coding genetic variation influences gene expression remain only partially understood but are considered to be major determinants of phenotypic diversity and disease risk. Here, we evaluated effects of >50 million SNPs and InDels provided by five inbred strains of mice on the responses of macrophages to interleukin 4 (IL-4), a cytokine that plays pleiotropic roles in immunity and tissue homeostasis. Remarkably, of >600 genes induced >2-fold by IL-4 across the five strains, only 26 genes reached this threshold in all strains. By applying deep learning and motif mutation analyses to epigenetic data for macrophages from each strain, we identified the dominant combinations of lineage determining and signal-dependent transcription factors driving late enhancer activation. These studies further revealed mechanisms by which non-coding genetic variation influences absolute levels of enhancer activity and their dynamic responses to IL-4, thereby contributing to strain-differential patterns of gene expression and phenotypic diversity.

genomics↗