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

Sisi Chen; Binyun Ma; Xue Li; Kailang Zhang; Yankai Wei; Bei Du; Xun Liu; Ruihua Wei; Xiaorong Li; Hong Nian

doi:10.1016/j.isci.2022.105176

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

iScience. 2022 Sep 23;25(10):105176. doi: 10.1016/j.isci.2022.105176. eCollection 2022 Oct 21.

Authors

Sisi Chen¹, Binyun Ma², Xue Li¹, Kailang Zhang¹, Yankai Wei¹, Bei Du¹, Xun Liu¹, Ruihua Wei¹, Xiaorong Li¹, Hong Nian¹

Affiliations

¹ Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, China.
² Department of Medicine/Hematology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.

Abstract

Pathogenic Th17 cells drive autoimmune pathology, but the molecular mechanisms underlying Th17 pathogenicity remain poorly understood. Here, we have shown 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 pathogenesis in 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 miR-181a-5p in restraining autoimmunity and may provide a potential therapeutic target for uveitis treatment.

Keywords: Biological sciences; Immunology; Molecular biology.