Chen Chen, Zhang Weiqiao, Zhou Tingyue, Liu Qiuyuan, Han Chao, Huang Zonghui, Chen Si, Mei Qiao, Zhang Cunjin, Zhang Kaiguang, Ma Hongdi, Zhou Rongbin, Jiang Wei, Pan Wen, Zhu Shu
Department of Digestive Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China; Institute of Immunology, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Cell Rep. 2022 Nov 29;41(9):111741. doi: 10.1016/j.celrep.2022.111741.
Metabolic rewiring is essential for Th17 cells' functional identity to sense and interpret environmental cues. However, the environmental metabolic checkpoints with specific regulation of Th17 cells, manifesting potential therapeutic opportunities to autoimmune diseases, remain largely unknown. Here, by screening more than one hundred compounds derived from intestinal microbes or diet, we found that vitamin B5 (VB5) restrains Th17 cell differentiation as well as related autoimmune diseases such as experimental autoimmune encephalomyelitis and colitis. Mechanistically, VB5 is catabolized into coenzyme A (CoA) in a pantothenate kinase (PANK)-dependent manner, and in turn, CoA binds to pyruvate kinase isoform 2 (PKM2) to impede its phosphorylation and nuclear translocation, thus inhibiting glycolysis and STAT3 phosphorylation. In humans, reduced serum VB5 levels are found in both IBD and MS patients. Collectively, our study demonstrates a role of VB5 in Th17 cell metabolic reprograming, thus providing a potential therapeutic intervention for Th17 cell-associated autoimmune diseases.
代谢重编程对于辅助性T细胞17（Th17）细胞感知和解读环境信号的功能特性至关重要。然而，对Th17细胞具有特定调节作用的环境代谢检查点在很大程度上仍不为人所知，而这些检查点可能为自身免疫性疾病带来潜在的治疗机会。在此，通过筛选一百多种源自肠道微生物或饮食的化合物，我们发现维生素B5（VB5）可抑制Th17细胞分化以及相关自身免疫性疾病，如实验性自身免疫性脑脊髓炎和结肠炎。从机制上讲，VB5以泛酸激酶（PANK）依赖的方式分解代谢为辅酶A（CoA），进而CoA与丙酮酸激酶同工酶2（PKM2）结合，阻碍其磷酸化和核转位，从而抑制糖酵解和信号转导及转录激活因子3（STAT3）磷酸化。在人类中，炎症性肠病（IBD）和多发性硬化症（MS）患者的血清VB5水平均降低。总体而言，我们的研究证明了VB5在Th17细胞代谢重编程中的作用，从而为Th17细胞相关的自身免疫性疾病提供了一种潜在的治疗干预措施。
