MYC-mediated silencing of miR-181a-5p promotes pathogenic Th17 responses by modulating AKT3-FOXO3 signaling

Pathogenic Th17 cells drive autoimmune pathology, but the molecular mechanisms underlying Th17 pathogenicity remain poorly understood. Here, we haves hown that miR-181a-5p was significantly decreased in pathogenic Th17 cells, and it negatively regulated pathogenic Th17 cell responses in vitro and in vivo. Th17 cells overexpressing miR-181a-5p exhibited impaired ability to induce pathogenesisin an adoptive transfer model of experimental autoimmune uveitis (EAU). Mechanistically, miR-181a-5p directly targeted AKT3, diminishing AKT3-mediated phosphorylation of FOXO3, and thereby activating FOXO3, a transcriptional repressor of pathogenic Th17 cell program. Supporting this,decreasing miR-181a-5p and up-regulated AKT3 expression were found in uveitis patients. Furthermore, intravitreal administration of miR-181a-5p mimics in mice effectively attenuated clinical and pathological signs of established EAU. Collectively,our results reveal a previously unappreciated T cell-intrinsic role of miR181a-5pin restraining autoimmunity and may provide a potential therapeutic target for uveitis treatment.

Automated summary

This study reveals that miR-181a-5p negatively regulates pathogenic Th17 cell responses by targeting AKT3 and activating FOXO3. Decreased miR-181a-5p and up-regulated AKT3 expression were found in uveitis patients. Intravitreal administration of miR-181a-5p mimics effectively attenuated clinical and pathological signs of established uveitis.