SerpinB1, previously known as MNEI (monocyte/neutrophil elastase inhibitor), has been well established to maintain the survival of neutrophils. Our recent studies showed that SerpinB1 is also the signature gene of IL-17-producing γδT cells and Th17 cells, and its expression is maintained by IL-23 signaling. Deficiency of SerpinB1 largely ameliorates the experimental autoimmune encephalomyelitis (EAE) with enhanced granule protease-mediated mitochondrial damage leading to suicidal cell death of pathogenic CD4 T cells. However, the mechanism that induces SerpinB1 expression in Th17 cells still remains elusive. Here, we showed that SerpinB1 was induced in Th17 cells, and plays a pivotal role to maintain the pathogenic signature of IL-23-primed Th17 cells in vitro. Its expression in Th17 cells was independent of Th17-lineage specific transcript factor retinoic acid-related orphan receptor γ t (RORγt), but was controlled by glycolysis and the mammalian target of rapamycin (mTOR) signaling. Finally, by using two specific pharmacological inhibitors, our study further deciphered that hypoxia-inducible factor 1α (HIF-1α) specifically controlled the SerpinB1 expression in Th17 cells. On the other side, when HIF-1α stabilizer Dimethyloxalylglycine (DMOG) was applied, SerpinB1 expression was significantly increased in Th17 cells. Taken together, this study is the first to report that SerpinB1 expression in Th17 cells is mediated by glycolysis/mTOR/HIF-1α pathway.

SerpinB1，以前称为MNEI（单核细胞/中性粒细胞弹性蛋白酶抑制剂），已经建立，可以维持中性粒细胞的存活。我们最近的研究表明，SerpinB1也是产生IL-17的γδT细胞和Th17细胞的标志基因，其表达通过IL-23信号传导得以维持。SerpinB1的缺乏大大改善了实验性自身免疫性脑脊髓炎（EAE），增强了颗粒蛋白酶介导的线粒体损伤，导致致病性CD4 T细胞自杀性细胞死亡。但是，在Th17细胞中诱导SerpinB1表达的机制仍然不清楚。在这里，我们表明SerpinB1在Th17细胞中被诱导，并在维持IL-23引发的Th17细胞在体外的致病性标志中起关键作用。。它在Th17细胞中的表达独立于Th17谱系特异性转录因子视黄酸相关的孤儿受体γt（RORγt），但受糖酵解和雷帕霉素（mTOR）信号转导的哺乳动物靶点控制。最后，通过使用两种特定的药理抑制剂，我们的研究进一步破译了缺氧诱导因子1α（HIF-1α）特异性控制Th17细胞中SerpinB1的表达。另一方面，当应用HIF-1α稳定剂二甲基草酰甘氨酸（DMOG）时，在Th17细胞中SerpinB1表达显着增加。综上所述，该研究是第一个报道Th17细胞中SerpinB1表达是通过糖酵解/ mTOR /HIF-1α途径介导的研究。