Effect of Dipyridamole on Experimental Autoimmune Uveitis: Reprogrammed Immune Cell Landscape and Reduced Th17 Pathogenicity.

ABSTRACT:

Purpose

Noninfectious uveitis is a sight-threatening autoimmune eye disease lacking effective targeted therapies. Dipyridamole (DIP), a phosphodiesterase (PDE) inhibitor, has demonstrated anti-inflammatory properties in inflammatory diseases. However, its application in uveitis remains unexplored.

Methods

We used single-cell RNA sequencing (scRNA-seq) data from experimental autoimmune uveitis (EAU) mice and uveitis patients to assess the potential association of PDE gene expression with disease development. Subsequently, EAU mice received oral DIP (300 mg/kg/day), starting at different time points (preventative, early-therapeutic, or late-therapeutic), and treatment efficacy was assessed. To explore immune components and signaling changes, we profiled cervical draining lymph nodes (CDLNs) from control, EAU, and DIP-treated mice by scRNA-seq and validated key findings with additional experiments. Mechanistically, pharmacologic interventions (an adenylyl cyclase inhibitor and the STAT3 agonist) were used in vitro.

Results

Expression of several PDE genes correlated with uveitis severity in both human and mouse. Preventative DIP treatment most effectively reduced fundus inflammation in EAU and modulated the Teff/Treg ratio in the CDLNs and spleens. In vitro, DIP suppressed CD4+ T cell proliferation, and inhibited pathogenic Teff. scRNA-seq analysis revealed that DIP partially reversed EAU-induced transcriptional alterations, with notable changes in immune cell composition and pathway activity. Mechanistically, DIP downregulated STAT3 activity and PIM1 expression in Th17 cells via cAMP, suggesting the involvement of the cAMP-STAT3-PIM1 axis in modulating immune homeostasis.

Conclusions

DIP ameliorated intraocular inflammation, modulated Th17/Treg balance, and reduced Th17 pathogenicity in EAU, potentially via cAMP-STAT3-PIM1 signaling. These findings highlight DIP as a promising therapeutic candidate for autoimmune uveitis.

SUBMITTER: Chen B 

PROVIDER: S-EPMC12697703 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature