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Resting CD4+ T cells exposed to oleic acid upregulate genes involved in immunometabolism resulting in increased IL-9+ frequencies post-activation [RNA-seq]

ABSTRACT: T cells are the most common immune cell in atherosclerotic plaques. Furthermore, T cell function is influenced by fatty acids that are abundant in the circulation and atherosclerotic plaques. Here, we define the effect of oleic acid, one of the most abundant fatty acids in the human circulation, on the transcriptome of resting CD4+ T cells and subsequently the polarization of the cells into T cell subsets post-activation. We first performed RNA sequencing of resting CD4+ T cells from 9 donors after 0.5, 3, 24, 48, and 72 hours exposure to 30µg/mL oleic acid. This revealed the upregulation of genes involved in cholesterol biosynthesis (HMGCR, SQLE, MVD and MVK) and de novo fatty acid biosynthesis (ACACA and FASN). Both pathways point to a metabolic reprogramming of the cells towards a pro-inflammatory state. Subsequently, a 26-marker spectral flow cytometry panel showed increased frequencies of IL-9+ and IL-17A+ cells among activated CD4+ T cells pre-exposed to oleic acid. IL-9 and IL-17A are primarily produced by the respective T helper (TH) subsets TH9 and TH17, where, especially TH9, has been implicated in the aggravation of atherosclerosis. Our data shows that oleic acid may induce a shift in immunometabolism in resting CD4+ T cells towards an activated profile that leads to more pro-inflammatory and pro-atherogenic polarization of these cells post-activation. Taken together, our study signals a potential role for the interaction between circulating fatty acids and CD4+ T cells in the development and pathogenesis of atherosclerosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE231458 | GEO | 2024/02/13

REPOSITORIES: GEO

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Project description:IL-17A is a pro-inflammatory cytokine that promotes host defense against infections and contributes to the pathogenesis of chronic inflammatory diseases. Dendritic cells (DC) are antigen-presenting cells responsible for adaptive immune responses. Here, we report that IL-17A induces intense remodeling of lipid metabolism in human monocyte-derived DC, as revealed by microarrays analysis. In particular NR1H3/LXR-a and its target genes were significantly upregulated in response to IL-17A. IL-17A induced accumulation of Oil Red O-positive lipid droplets in DC leading to the generation of lipid-laden DC. A lipidomic study established that all the analyzed lipid species, i.e phospholipids, cholesterol, triglycerides, cholesteryl esters were elevated in IL-17A-treated DC. The increased expression of membrane lipid transporters in IL-17A-treated DC as well as their enhanced ability to uptake the fatty acid Bodipy-FL-C16 suggested that lipid uptake was the main mechanism responsible for lipid accumulation in response to IL-17A. IL-17A-induced lipid laden DC were able to stimulate allogeneic T cell proliferation in vitro as efficiently as untreated DC, indicating that IL-17A-treated DC are potently immunogenic. This study, encompassed in the field of immunometabolism, points out for the first time IL-17A as a modulator of lipid metabolism in DC and provides a rationale to delineate the importance of lipid-laden DC in IL-17A-related inflammatory diseases. We used microarrays analysis to understand the impact of IL-17A on human monocyte-derived human dendritic cells. We found overexpression of many genes involved in lipid metabolism in IL-17A-treated dendritic cells compared to untreated dendritic cells. In particular NR1H3/LXR-a and its target genes were significantly upregulated in response to IL-17A. IL-17A induced accumulation of Oil Red O-positive lipid droplets in DC leading to the generation of lipid-laden DC. A lipidomic study established that all the analyzed lipid species, i.e phospholipids, cholesterol, triglycerides, cholesteryl esters were elevated in IL-17A-treated DC. The increased expression of membrane lipid transporters in IL-17A-treated DC as well as their enhanced ability to uptake the fatty acid Bodipy-FL-C16 suggested that lipid uptake was the main mechanism responsible for lipid accumulation in response to IL-17A. IL-17A-induced lipid laden DC were able to stimulate allogeneic T cell proliferation in vitro as efficiently as untreated DC, indicating that IL-17A-treated DC are potently immunogenic. This study, encompassed in the field of immunometabolism, points out for the first time IL-17A as a modulator of lipid metabolism in DC and provides a rationale to delineate the importance of lipid-laden DC in IL-17A-related inflammatory diseases. RNA was extracted from untreated in vitro-generated DC at day 0 (DC, 4 biological replicates ) or DC cultured for 12 days with IL-17A, in the absence or presence of IFN-g (DC-17 and DC-G17, 5 biological replicates)

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Resting CD4+ T cells exposed to oleic acid upregulate genes involved in immunometabolism resulting in increased IL-9+ frequencies post-activation [RNA-seq]

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