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Elevated O‐GlcNAc Exacerbates Pro‐Inflammatory Cytokine Secretion from CD4 + T cells
Author(s) -
Machacek Miranda,
Li Jibiao,
Li Tiangang,
Lydic Todd,
Slawson Chad,
Fields Patrick
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.673.9
Subject(s) - endocrinology , medicine , secretion , inflammation , cytokine , chemistry , t cell , biology , immunology , immune system
Chronic inflammation is a feature of obesity and enhances the risk of atherosclerosis, cancer, diabetes, and autoimmunity. Specifically, pro‐inflammatory T H 17 CD4 + effector T cells are increased in metabolic diseases. However, a clear molecular mechanism linking metabolic changes with pro‐inflammatory T cells is lacking. We hypothesize that elevated levels of O‐linked β‐N‐acetylglucosamine (O‐GlcNAc), a post‐translational modification of nuclear and cytoplasmic proteins, promotes pro‐inflammatory CD4+ T cell function. Since production of O‐GlcNAc involves input from carbohydrate, amino acid, fatty acid, and nucleic acid metabolism, the modification acts as a sensor of a cell's nutritional status. To investigate the role of O‐GlcNAc in a setting of metabolic disease, we analyzed O‐GlcNAc levels in CD4 + T cells from mice fed a high fat and cholesterol “Western” diet. Naïve CD4 + T cells from obese mice have elevated O‐GlcNAc levels compared to cells from mice fed standard chow. When polarized to a T H 17 lineage, cells from obese mice secrete more IL‐17A, the eponymous T H 17 cytokine. Importantly, when naïve CD4 + T cells from lean and obese mice are polarized to a T H 17 lineage in the presence of Thiamet‐G (TMG, an inhibitor of the enzyme that removes O‐GlcNAc (O‐GlcNAcase, OGA)) the cells from lean mice secrete levels of IL‐17 comparable to those from obese mice and IL‐17 secretion was exacerbated in cells from obese mice. Transcript levels of IL‐17 are similarly elevated in both lean and obese mice T H 17 cells treated with TMG. RORγt (retinoic acid‐related orphan receptor gamma) acts as the T H 17 master transcription factor, orchestrating the T H 17 differentiation program. Uniquely among the CD4 + effector T cell master transcription factors, RORγt is regulated by fatty acid ligands which promote or repress its activity. Acetyl CoA carboxylase 1 (ACC1), the rate limiting enzyme in fatty acid synthesis, is known to enhance generation of T H 17 cells by producing ligands that increase the activity of RORγt. We discovered that ACC1 is O‐GlcNAcylated. Furthermore, lipidomics analysis identified clear differences in the lipid environment of T cells isolated from lean and obese mice −/+ TMG. Thus, abnormally elevated O‐GlcNAc levels may favor the generation of ligands that enhance RORγt activity at the IL‐17 promoter. More directly implicating O‐GlcNAc's regulation of RORγt, chromatin immunoprecipation of RORγt and O‐GlcNAc transferase (OGT, the enzyme that modifies proteins with O‐GlcNAc) at the IL‐17 promoter and an enhancer, CNS2 (conserved noncoding sequence 2), is increased with TMG treatment. Collectively, our data suggest that elevated O‐GlcNAc levels increase pro‐inflammatory IL‐17 secretion from T H 17 cells through alteration of the lipidome and direct effects on the IL‐17 promoter complex. Further study into the molecular mechanism of how O‐GlcNAcylation promotes pro‐inflammatory T H 17 T cell function will provide insight into how nutritional excess worsens inflammation. Support or Funding Information This research was supported by NIH grant R01DK100595‐01, NIH grant R01DK091277‐03, COBRE P30GM122731, and a KUMC Institute of Reproductive Health and Regenerative Medicine pilot grant. MM is supported by a KUMC Biomedical Research Training Program grant.Elevated O‐GlcNAc increases pro‐inflammatory IL‐17 cytokine secretion from T H 17 cellsThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

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