Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
Center for Research in Inflammatory Diseases, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
J Exp Med. 2020 Oct 5;217(10). doi: 10.1084/jem.20190613.
Th17 cell differentiation and pathogenicity depend on metabolic reprogramming inducing shifts toward glycolysis. Here, we show that the pyruvate kinase M2 (PKM2), a glycolytic enzyme required for cancer cell proliferation and tumor progression, is a key factor mediating Th17 cell differentiation and autoimmune inflammation. We found that PKM2 is highly expressed throughout the differentiation of Th17 cells in vitro and during experimental autoimmune encephalomyelitis (EAE) development. Strikingly, PKM2 is not required for the metabolic reprogramming and proliferative capacity of Th17 cells. However, T cell-specific PKM2 deletion impairs Th17 cell differentiation and ameliorates symptoms of EAE by decreasing Th17 cell-mediated inflammation and demyelination. Mechanistically, PKM2 translocates into the nucleus and interacts with STAT3, enhancing its activation and thereby increasing Th17 cell differentiation. Thus, PKM2 acts as a critical nonmetabolic regulator that fine-tunes Th17 cell differentiation and function in autoimmune-mediated inflammation.
Th17 细胞的分化和致病性取决于诱导糖酵解向糖酵解转变的代谢重编程。在这里，我们表明，丙酮酸激酶 M2（PKM2），一种促进癌细胞增殖和肿瘤进展的糖酵解酶，是介导 Th17 细胞分化和自身免疫性炎症的关键因素。我们发现，PKM2 在体外 Th17 细胞的分化过程中和实验性自身免疫性脑脊髓炎（EAE）发展过程中高度表达。引人注目的是，PKM2 不是 Th17 细胞代谢重编程和增殖能力所必需的。然而，T 细胞特异性 PKM2 缺失通过减少 Th17 细胞介导的炎症和脱髓鞘，损害 Th17 细胞分化并改善 EAE 的症状。在机制上，PKM2 易位到细胞核并与 STAT3 相互作用，增强其激活，从而增加 Th17 细胞分化。因此，PKM2 作为一种关键的非代谢调节剂，精细调节自身免疫介导的炎症中的 Th17 细胞分化和功能。
Zotero 插件
