De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells
De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells
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DOI：
10.1038/nm.3704
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发表时间：
2014-11-01
期刊：
影响因子：
82.9
通讯作者：
Sparwasser, Tim
中科院分区：
文献类型：
--
作者：
Berod, Luciana;Friedrich, Christin;Sparwasser, Tim
辅助 T 细胞 17 (T(H)17) 谱系的白细胞介素 17 (IL-17) 分泌 T 细胞在多种炎症和自身免疫性疾病中发挥致病作用，因此是治疗干预的一个极具吸引力的靶点。我们报道，抑制乙酰辅酶A羧化酶1 (ACC1) 可抑制人和小鼠T(H)17 细胞的形成，并促进抗炎Foxp(3+) 调节性T (T-reg) 细胞的发育。我们发现，T(H)17 细胞（而非 Treg 细胞）的发育依赖于 ACC1 介导的从头脂肪酸合成和潜在的糖酵解-脂肪生成代谢途径。尽管 T(H)17 细胞利用此途径产生细胞膜所需的磷脂，但 Treg 细胞很容易为此目的吸收外源脂肪酸。值得注意的是，ACC1 的药理抑制或 T 细胞特异性删除不仅会阻断脂肪酸从头合成，还会干扰糖酵解和三羧酸循环中葡萄糖衍生碳的代谢通量。在体内，用 ACC 特异性抑制剂 soraphen A 治疗或 T 细胞特异性删除 ACC1 可以减轻 T(H)17 细胞介导的自身免疫性疾病。我们的结果表明，T(H)17 细胞和 Treg 细胞在依赖 ACC1 介导的从头脂肪酸合成方面存在根本差异，这可能被用作 T(H)17 细胞介导的炎症性疾病代谢免疫调节的新策略。
Interleukin-17 (IL-17)-secreting T cells of the T helper 17 (T(H)17) lineage play a pathogenic role in multiple inflammatory and autoimmune conditions and thus represent a highly attractive target for therapeutic intervention. We report that inhibition of acetyl-CoA carboxylase 1 (ACC1) restrains the formation of human and mouse T(H)17 cells and promotes the development of anti-inflammatory Foxp(3+) regulatory T (T-reg) cells. We show that T(H)17 cells, but not Treg cells, depend on ACC1-mediated de novo fatty acid synthesis and the underlying glycolytic-lipogenic metabolic pathway for their development. Although T(H)17 cells use this pathway to produce phospholipids for cellular membranes, Treg cells readily take up exogenous fatty acids for this purpose. Notably, pharmacologic inhibition or T cell-specific deletion of ACC1 not only blocks de novo fatty acid synthesis but also interferes with the metabolic flux of glucose-derived carbon via glycolysis and the tricarboxylic acid cycle. In vivo, treatment with the ACC-specific inhibitor soraphen A or T cell-specific deletion of ACC1 in mice attenuates T(H)17 cell-mediated autoimmune disease. Our results indicate fundamental differences between T(H)17 cells and Treg cells regarding their dependency on ACC1-mediated de novo fatty acid synthesis, which might be exploited as a new strategy for metabolic immune modulation of T(H)17 cell-mediated inflammatory diseases.