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Itaconate regulates Th17/Treg cell balance via metabolic and epigenetic reprogramming

ABSTRACT: An imbalance of T helper (Th17) cells and regulatory T (Treg) cells contributes to the pathogenesis of autoimmune diseases. The endogenous metabolite itaconate (ITA) is a regulator of macrophages; however, its role in T cells regulation is unclear. Here, we show that ITA inhibited Th17 cell differentiation and promoted Treg cell differentiation via metabolic and epigenetic reprogramming. Mechanistically, ITA suppressed glycolysis and mitochondrial respiration in Th17 and Treg-polarizing T cells. In Th17 cells, the S-adenosyl-L-methionine/ S-adenosylhomocysteine ratio was decreased following ITA administration in vitro, subsequently altering the epigenetic status. Further, ITA inhibited RORγt binding at the Il17a promoter, resulting in reduced IL-17A expression. In Treg cells, ITA reduced 2-hydroxyglutarate levels, which suppressed Foxp3 expression. The adoptive transfer of ITA-treated Th17-polarizing T cells ameliorated experimental autoimmune encephalomyelitis. Collectively, these results indicate that ITA serves as a crucial metabolic regulator for Th17/Treg cell balance and a potential therapeutic agent against autoimmune diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE182895 | GEO | 2023/01/18

REPOSITORIES: GEO

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Itaconate regulates Th17/Treg cell balance via metabolic and epigenetic reprogramming [ATAC-seq]

Project description:An imbalance of T helper (Th17) cells and regulatory T (Treg) cells contributes to the pathogenesis of autoimmune diseases. The endogenous metabolite itaconate (ITA) is a regulator of macrophages; however, its role in T cells regulation is unclear. Here, we show that ITA inhibited Th17 cell differentiation and promoted Treg cell differentiation via metabolic and epigenetic reprogramming. Mechanistically, ITA suppressed glycolysis and mitochondrial respiration in Th17 and Treg-polarizing T cells. In Th17 cells, the S-adenosyl-L-methionine/ S-adenosylhomocysteine ratio was decreased following ITA administration in vitro, subsequently altering the epigenetic status. Further, ITA inhibited RORγt binding at the Il17a promoter, resulting in reduced IL-17A expression. In Treg cells, ITA reduced 2-hydroxyglutarate levels, which suppressed Foxp3 expression. The adoptive transfer of ITA-treated Th17-polarizing T cells ameliorated experimental autoimmune encephalomyelitis. Collectively, these results indicate that ITA serves as a crucial metabolic regulator for Th17/Treg cell balance and a potential therapeutic agent against autoimmune diseases.

2023-01-18 | GSE207941 | GEO

HIF1a-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells

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Epigenetic initiation of the Th17 differentiation programme is promoted by Cxxc finger protein 1

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