SerpinB1 expression in Th17 cells depends on hypoxia-inducible factor 1-alpha.

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.