Itaconate ameliorates autoimmunity by modulating T cell imbalance via metabolic and epigenetic reprogramming

Kuniyuki Aso, Michihito Kono*, Masatoshi Kanda, Yuki Kudo, Kodai Sakiyama, Ryo Hisada, Kohei Karino, Yusho Ueda, Daigo Nakazawa, Yuichiro Fujieda, Masaru Kato, Olga Amengual, Tatsuya Atsumi

*この論文の責任著者

研究成果: ジャーナルへの寄稿学術論文査読

70 被引用数 (Scopus)

抄録

Dysregulation of Th17 and Treg cells contributes to the pathophysiology of many autoimmune diseases. Herein, we show that itaconate, an immunomodulatory metabolite, inhibits Th17 cell differentiation and promotes Treg cell differentiation by orchestrating metabolic and epigenetic reprogramming. Mechanistically, itaconate suppresses glycolysis and oxidative phosphorylation in Th17- and Treg-polarizing T cells. Following treatment with itaconate, the S-adenosyl-L-methionine/S-adenosylhomocysteine ratio and 2-hydroxyglutarate levels are decreased by inhibiting the synthetic enzyme activities in Th17 and Treg cells, respectively. Consequently, these metabolic changes are associated with altered chromatin accessibility of essential transcription factors and key gene expression in Th17 and Treg cell differentiation, including decreased RORγt binding at the Il17a promoter. The adoptive transfer of itaconate-treated Th17-polarizing T cells ameliorates experimental autoimmune encephalomyelitis. These results indicate that itaconate is a crucial metabolic regulator for Th17/Treg cell balance and could be a potential therapeutic agent for autoimmune diseases.

本文言語英語
論文番号984
ジャーナルNature Communications
14
1
DOI
出版ステータス出版済み - 2023/12

ASJC Scopus 主題領域

  • 化学一般
  • 生化学、遺伝学、分子生物学一般
  • 物理学および天文学一般

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