FoxO1 promotes high glucose-induced inflammation and cataract formation via JAK1/STAT1.

Abstract

Purpose: To investigate whether in diabetic cataract (DC), FoxO1 regulates high glucose (HG)-induced activation of NLRC4/IL-6 inflammatory mediators in human lens epithelial cells (SRA01/04) via the JAK1/STAT1 pathway, leading to cataract formation.

Methods: Expression levels of FoxO1, inflammatory factor IL-6 and inflammatory vesicle NLRC4 were examined in SRA01/04 under high glucose (HG) stress at 25-150 mM. Rat lenses were also cultured using HG medium with or without the addition of the FoxO1 inhibitor AS1842856 and the JAK1 agonist RO8191. 5.5 mM glucose concentration group (NG) was used as a control. Real-time PCR, Western blots, and immunofluorescent staining evaluated the mRNA and protein levels of FoxO1, NLRC4, and IL-6. Apoptosis, cell viability, and EDU Staining were also assessed.

Results: HG stimulation induced elevated FoxO1 expression and caused NLRC4/IL-6 activation in a concentration-dependent manner. Whereas knockdown of FoxO1 inhibited the high expression of NLRC4/IL-6 inflammatory mediators in response to HG stimulation. The growth of SRA01/04 was inhibited under HG condition, and the cell proliferation ability was restored and even promoted by knocking out FoxO1. HG incubation of rat lens resulted in lens clouding and cataract formation, which was prevented by AS1842856 treatment and reversed by RO8191.

Conclusion: FoxO1 positively regulates HG-induced SRA01/04 inflammatory activation through the JAK1/STAT1 pathway and promotes DC. This provides a feasible strategy for the treatment of diabetic cataract.