Foxo1 Drives the TGFß1-Dependent Dichotomy of Th17 Cell Fates.

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 (TGFß1) is pivotal for the differentiation of non-pathogenic Th17 cells, the role of TGFß3 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 TGFß1 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 TGFß1 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 TGFß1-dependent manner. Suggest that targeting Foxo1 could be a promising therapeutic strategy for autoimmune diseases.

Aflatoxin B1 impairs leydig cells through inhibiting AMPK/mTOR-mediated autophagy flux pathway.

Aflatoxin B1 (AFB1), a potential endocrine disrupter, has been shown to induce hepatotoxicity in animal models, but the effects of AFB1 on Leydig cell function are unclear. In this study, in vivo exposure to AFB1 at 15 and 150 µg/kg/day lowered serum testosterone (T), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels, reduced Leydig cell number, and down-regulated the expression of testosterone biosynthesis-related genes. In vitro study showed that AFB1 (10 µM) significantly increased ROS levels, and decreased T production in Leydig cells by suppressing certain T-biosynthesis gene expressions. Moreover, AFB1 induced Leydig cell apoptosis through lowering pAMPK/AMPK ratio and increasing pmTOR/mTOR ratio, and then further up-regulating autophagy and apoptosis proteins, LC3, BECLIN 1, and BAX, as well as down-regulating autophagy flux protein P62 and anti-apoptosis protein BCL-2. AFB1-induced toxicity in Leydig cells was characterized by inhibiting T-biosynthesis gene expression, reducing Leydig cell number, promoting ROS production, and inducing cell apoptosis via suppressing AMPK/mTOR-mediated autophagy flux pathway.