Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
Proc Natl Acad Sci U S A. 2018 Sep 11;115(37):9288-9293. doi: 10.1073/pnas.1805717115. Epub 2018 Aug 27.
Th17 cells favor glycolytic metabolism, and pyruvate dehydrogenase (PDH) is the key bifurcation enzyme, which in its active dephosphorylated form advances the oxidative phosphorylation from glycolytic pathway. The transcriptional factor, inducible cAMP early repressor/cAMP response element modulator (ICER/CREM), has been shown to be induced in Th17 cells and to be overexpressed in CD4 T cells from the patients with systemic lupus erythematosus (SLE). We found that glycolysis and lactate production in in vitro Th17-polarized T cells was reduced and that the expression of pyruvate dehydrogenase phosphatase catalytic subunit 2 (PDP2), an enzyme that converts the inactive PDH to its active form, and PDH enzyme activity were increased in Th17 cells from ICER/CREM-deficient animals. ICER was found to bind to the promoter and suppress its expression. Furthermore, forced expression of PDP2 in CD4 cells reduced the in vitro Th17 differentiation, whereas shRNA-based suppression of PDP2 expression increased in vitro Th17 differentiation and augmented experimental autoimmune encephalomyelitis. At the translational level, PDP2 expression was decreased in memory Th17 cells from patients with SLE and forced expression of PDP2 in CD4 T cells from lupus-prone MRL/ mice and patients with SLE suppressed Th17 differentiation. These data demonstrate the direct control of energy production during Th17 differentiation in health and disease by the transcription factor ICER/CREM at the PDH metabolism bifurcation level.
Th17 细胞倾向于糖酵解代谢，而丙酮酸脱氢酶 (PDH) 是关键的分支酶，它在去磷酸化的活性形式下将氧化磷酸化从糖酵解途径推进。转录因子，诱导型 cAMP 早期阻遏物/cAMP 反应元件调节剂 (ICER/CREM)，已被证明在 Th17 细胞中被诱导，并在系统性红斑狼疮 (SLE) 患者的 CD4 T 细胞中过度表达。我们发现体外 Th17 极化 T 细胞中的糖酵解和乳酸生成减少，并且在 ICER/CREM 缺陷动物的 Th17 细胞中，丙酮酸脱氢酶磷酸酶催化亚基 2 (PDP2) 的表达增加，该酶将无活性的 PDH 转化为其活性形式，并且 PDH 酶活性增加。发现 ICER 与启动子结合并抑制其表达。此外，在 CD4 细胞中强制表达 PDP2 可减少体外 Th17 分化，而基于 shRNA 的 PDP2 表达抑制可增加体外 Th17 分化并增强实验性自身免疫性脑脊髓炎。在翻译水平上，SLE 患者记忆性 Th17 细胞中的 PDP2 表达减少，而在狼疮易感 MRL/ 小鼠和 SLE 患者的 CD4 T 细胞中强制表达 PDP2 可抑制 Th17 分化。这些数据表明，转录因子 ICER/CREM 在 PDH 代谢分支水平上直接控制健康和疾病中 Th17 分化期间的能量产生。
