Abstract
Chronic, low-grade inflammation increases the risk for atherosclerosis, cancer, and autoimmunity in diseases such as obesity and diabetes. Levels of CD4+ T helper 17 (Th17) cells, which secrete interleukin 17A (IL-17A), are increased in obesity and contribute to the inflammatory milieu; however, the relationship between signaling events triggered by excess nutrient levels and IL-17A-mediated inflammation is unclear. Here, using cytokine, quantitative real-time PCR, immunoprecipitation, and ChIP assays, along with lipidomics and MS-based approaches, we show that increased levels of the nutrient-responsive, post-translational protein modification, O-GlcNAc, are present in naive CD4+ T cells from a diet-induced obesity murine model and that elevated O-GlcNAc levels increase IL-17A production. We also found that increased binding of the Th17 master transcription factor RAR-related orphan receptor γ t variant (RORγt) at the IL-17 gene promoter and enhancer, as well as significant alterations in the intracellular lipid microenvironment, elevates the production of ligands capable of increasing RORγt transcriptional activity. Importantly, the rate-limiting enzyme of fatty acid biosynthesis, acetyl-CoA carboxylase 1 (ACC1), is O-GlcNAcylated and necessary for production of these RORγt-activating ligands. Our results suggest that increased O-GlcNAcylation of cellular proteins may be a potential link between excess nutrient levels and pathological inflammation.
Highlights
Chronic, low-grade inflammation increases the risk for atherosclerosis, cancer, and autoimmunity in diseases such as obesity and diabetes
To determine whether O-GlcNAc plays a role in the function of T cell effectors, we treated murine, splenic CD4ϩ T cells ex vivo with thiamet-G (TMG), a highly specific OGA inhibitor [22], for 6 h before activation under nonpolarizing conditions (Th0) or, in other words, without cytokines that would induce polarization toward a specific CD4ϩ T cell lineage (Th1, Th2, etc.)
Production of interleukin 17A (IL-17A), the major cytokine secreted by T helper 17 (Th17) cells, doubled (Fig. 1B)
Summary
Low-grade inflammation increases the risk for atherosclerosis, cancer, and autoimmunity in diseases such as obesity and diabetes. Levels of CD4؉ T helper 17 (Th17) cells, which secrete interleukin 17A (IL-17A), are increased in obesity and contribute to the inflammatory milieu; the relationship between signaling events triggered by excess nutrient levels and IL-17A–mediated inflammation is unclear. Activation of naive CD4ϩ T cells in response to a pathogen prompts their differentiation into various effectors Major metabolic shifts occur during activation and are required for effector cell function. Th17 cells have a requirement for endogenous fatty acid synthesis, and pharmacological inhibition or genetic deletion of acetyl-CoA carboxylase 1 (ACC1) inhibits Th17 and favors Treg differentiation [7]. Inflammatory Th17 cells infiltrating the synovium of joints in a rheumatoid arthritis model accumulate lipid droplets due to increased fatty acid metabolism [9]. Mechanisms that clearly link excess nutrients with aberrant T cell function are unclear
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