MAFF mediates transcriptional activation of CFLAR to reduce regulatory T cell apoptosis and inhibit diabetic retinopathy progression

Background: Regulatory T cells (Tregs) regulate inflammation, promote regeneration, and may prevent diabetic retinopathy (DR). This study investigated whether MAFF inhibited DR progression by suppressing Treg Apoptosis through CFLAR activation.

Methods: Bioinformatics was utilized to predict differentially expressed genes in peripheral blood mononuclear cells from DR patients and type 2 diabetes mellitus patients. A mouse model of DR was induced through a high-fat diet and streptozotocin. Mice were subjected to genetic intervention of CFLAR overexpression to observe retinal vascular infiltration, retinal thickness, tight junction proteins, inflammatory factors, and Treg Apoptosis. Tregs were treated with high glucose (HG) and infected with CFLAR overexpression. Tregs were co-cultured with HMC3 cells to observe the activation of HMC3 cells. Bioinformatics was utilized to predict the upstream factor of CFLAR, and the transcriptional regulation between MAFF and CFLAR was verified. Tregs and DR mice were treated with MAFF overexpression and CFLAR knockdown to validate the mechanism.

Results: CFLAR and MAFF were lowly expressed in the Treg of DR mice. Overexpression of CFLAR or MAFF inhibited retinal vascular infiltration, increased retinal thickness, increased IL-10 levels, decreased TNF-α, IL-6, and VEGF levels, upregulated ZO-1 and Occludin, and promoted Tregs in the spleen in DR mice. Overexpression of CFLAR or MAFF weakened HG-induced Treg Apoptosis, promoted IL-10 secretion, reduced TNF-α and IL-6 secretion, and inhibited microglia activation. However, the combined knockdown of CFLAR promoted DR progression.

Conclusion: MAFF inhibits DR progression by reducing Treg Apoptosis through transcriptional activation of CFLAR.