| First Author | Zhang M | Year | 2024 |
| Journal | J Leukoc Biol | PubMed ID | 38193891 |
| Mgi Jnum | J:355125 | Mgi Id | MGI:7737856 |
| Doi | 10.1093/jleuko/qiae004 | Citation | Zhang M, et al. (2024) Foxo1 Drives the TGFbeta1-Dependent Dichotomy of Th17 Cell Fates. J Leukoc Biol |
| abstractText | T-helper 17 (Th17) cells play a dual role in immunological responses, serving as essential components in tissue homeostasis and host defense against microbial pathogens while also contributing to pro-inflammatory conditions and autoimmunity. While Transforming Growth Factor-beta 1 (TGFbeta1) is pivotal for the differentiation of non-pathogenic Th17 cells, the role of TGFbeta3 and Activin in steering Th17 cells toward a pathogenic phenotype has been acknowledged. However, the molecular mechanisms governing this dichotomy remain elusive. In this study, we demonstrate that the transcription factor Foxo1 is upregulated in a TGFbeta1 dose-dependent manner, serving as a critical regulator that specifically modulates the fate of pathogenic Th17 cells. Analyses in both uveitis patients and an Experimental Autoimmune Uveitis (EAU) mouse model reveal a strong correlation between disease severity and diminished Foxo1 expression levels. Ectopic expression of Foxo1 selectively attenuates IL-17A production under pathogenic Th17-inducing conditions. Moreover, enhanced Foxo1 expression, triggered by TGFbeta1 signaling, is implicated in fatty acid metabolism pathways that favor non-pathogenic Th17 differentiation. Our drug screening identifies several FDA-approved compounds can upregulate Foxo1. Collectively, our findings offer evidence that Foxo1 serves as a molecular switch to specifically control pathogenic versus non-pathogenic Th17 differentiation in a TGFbeta1-dependent manner. Suggest that targeting Foxo1 could be a promising therapeutic strategy for autoimmune diseases. |
