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

Dysregulation of T cell homeostasis is known to contribute to the immunopathology of autoimmune diseases. Here the authors show that itaconate impacts autoimmune pathology by altering T cells via modulation of metabolic and epigenetic programs. 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 ROR gamma t 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.

Automated summary

The study reveals that itaconate can alter T cell function and impact the development of autoimmune diseases through modulation of metabolic and epigenetic programs. Itaconate inhibits Th17 cell differentiation and promotes Treg cell differentiation by suppressing glycolysis and oxidative phosphorylation. The metabolic changes induced by itaconate also affect chromatin accessibility, transcription factor binding, and gene expression in Th17 and Treg cell differentiation. Furthermore, the adoptive transfer of itaconate-treated Th17 cells can ameliorate autoimmune encephalomyelitis. These findings suggest that itaconate is a crucial metabolic regulator for Th17/Treg cell balance and can be a potential therapeutic agent for autoimmune diseases.