miR-182-5p inhibits the pathogenic Th17 response in experimental autoimmune uveitis mice via suppressing TAF15

Background: CD4⁺ T helper 17 (Th17) cells play a contributory role in uveitis and other autoimmune disorders. However, less is understood about the contribution of microRNAs (miRNAs) in regulating the pathogenic Th17 response in uveitis.

Methods: The in vivo experimental autoimmune uveitis (EAU) model was constructed in female C57BL/6 mice. Primary EAU mouse CD4⁺ T-cells and the murine T-cell line EL4 were used for in vitro experiments. miRNA mimic/inhibitor, lentiviral overexpression plasmids, and small interfering RNAs (siRNAs) were used to modulate miR-182-5p and TAF15 expression. CD4⁺ T-cells from healthy controls (HC, n = 15), active Behçet's disease with uveitis (BD, n = 15), or active sympathetic ophthalmia with uveitis (SO, n = 15) were analyzed for miR-182-5p, TAF15, and Th17 marker gene expression.

Results: miR-182-5p was downregulated in EAU mouse-derived Th17 cells. miR-182-5p negatively regulated Th17 cell development in vitro. miR-182-5p mimic therapy in transplanted Th17 cells ameliorated EAU severity in vivo. Mechanistically, miR-182-5p directly inhibited the transcriptional initiator TATA-binding protein-associated factor 15 (TAF15, TAFII68). miR-182-5p's inhibition of TAF15 negatively regulated Th17 cell development by suppressing STAT3 phosphorylation. TAF15 and Th17 marker expression were positively correlated in CD4⁺ T-cells from BD and SO patients.

Conclusion: miR-182-5p mimic therapy inhibits the pathogenic Th17 response in EAU mice. miR-182-5p's inhibition of TAF15 negatively regulates Th17 cell development by suppressing STAT3 phosphorylation. As TAF15 shows a positive relationship with Th17 cell markers in uveitis patients, the miR-182-5p/TAF15 axis shows promise as a therapeutic target for uveitis.