| First Author | Qian Y | Year | 2021 |
| Journal | Cell Rep | Volume | 36 |
| Issue | 8 | Pages | 109602 |
| PubMed ID | 34433042 | Mgi Jnum | J:350601 |
| Mgi Id | MGI:6876852 | Doi | 10.1016/j.celrep.2021.109602 |
| Citation | Qian Y, et al. (2021) ZEB1 promotes pathogenic Th1 and Th17 cell differentiation in multiple sclerosis. Cell Rep 36(8):109602 |
| abstractText | Inappropriate CD4(+) T helper (Th) differentiation can compromise host immunity or promote autoimmune disease. To identify disease-relevant regulators of T cell fate, we examined mutations that modify risk for multiple sclerosis (MS), a canonical organ-specific autoimmune disease. This analysis identified a role for Zinc finger E-box-binding homeobox (ZEB1). Deletion of ZEB1 protects against experimental autoimmune encephalitis (EAE), a mouse model of multiple sclerosis (MS). Mechanistically, ZEB1 in CD4(+) T cells is required for pathogenic Th1 and Th17 differentiation. Genomic analyses of paired human and mouse expression data elucidated an unexpected role for ZEB1 in JAK-STAT signaling. ZEB1 inhibits miR-101-3p that represses JAK2 expression, STAT3/STAT4 phosphorylation, and subsequent expression of interleukin-17 (IL-17) and interferon gamma (IFN-gamma). Underscoring its clinical relevance, ZEB1 and JAK2 downregulation decreases pathogenic cytokines expression in T cells from MS patients. Moreover, a Food and Drug Administration (FDA)-approved JAK2 inhibitor is effective in EAE. Collectively, these findings identify a conserved, potentially targetable mechanism regulating disease-relevant inflammation. |
