Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Department of Rheumatology and Clinical Immunology, Sapporo Medical University, Sapporo, Japan.
Nat Commun. 2023 Feb 27;14(1):984. doi: 10.1038/s41467-023-36594-x.
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.
代谢物衣康酸通过调控代谢和表观遗传重编程抑制 Th17 细胞分化并促进 Treg 细胞分化。在此，我们展示了代谢物衣康酸，一种免疫调节代谢物，通过协调代谢和表观遗传重编程来抑制 Th17 细胞分化并促进 Treg 细胞分化。在机制上，衣康酸抑制 Th17 和 Treg 极化 T 细胞中的糖酵解和氧化磷酸化。用衣康酸处理后，通过抑制 Th17 和 Treg 细胞中合成酶的活性，分别降低 S-腺苷甲硫氨酸/S-腺苷同型半胱氨酸比和 2-羟戊二酸水平。因此，这些代谢变化与关键转录因子的染色质可及性以及 Th17 和 Treg 细胞分化中关键基因表达的改变相关，包括 Il17a 启动子处 RORγt 结合减少。用衣康酸处理过的 Th17 极化 T 细胞的过继转移可改善实验性自身免疫性脑脊髓炎。这些结果表明，衣康酸是 Th17/Treg 细胞平衡的关键代谢调节剂，可能是自身免疫性疾病的潜在治疗药物。
