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 and Tatsuya Atsumi
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Kuniyuki Aso: Hokkaido University
Michihito Kono: Hokkaido University
Masatoshi Kanda: Sapporo Medical University
Yuki Kudo: Hokkaido University
Kodai Sakiyama: Hokkaido University
Ryo Hisada: Hokkaido University
Kohei Karino: Hokkaido University
Yusho Ueda: Hokkaido University
Daigo Nakazawa: Hokkaido University
Yuichiro Fujieda: Hokkaido University
Masaru Kato: Hokkaido University
Olga Amengual: Hokkaido University
Tatsuya Atsumi: Hokkaido University

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-36594-x

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