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

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

  • Invest Ophthalmol Vis Sci. 2025 Dec 1;66(15):16. doi: 10.1167/iovs.66.15.16.
Binyao Chen 1,  Zhaohao Huang 2 3,  Junjie Chen 1,  Yi Wu 2 3,  Jianjie Lv 1,  Yingying Wen 4,  Xiaohang Wu 1,  Xulin Zhang 1,  Haotian Lin 1 5 6,  Wenru Su 1 7
Affiliations

Affiliations

  • 1 Zhongshan Ophthalmic Center, Sun Yat-Sen University, WHO Collaborating Centre for Eye Care and Vision, State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, China.
  • 2 Guangdong Eye Institute, Department of Ophthalmology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
  • 3 Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
  • 4 Bengbu Medical University, Bengbu, Anhui, China.
  • 5 Hainan Eye Hospital and Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Haikou, Hainan, China.
  • 6 Center for Precision Medicine and Department of Genetics and Biomedical Informatics, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
  • 7 Department of Ophthalmology, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
PMID: 41334959 DOI: 10.1167/iovs.66.15.16
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.

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