The pathophysiology of diabetic retinopathy involves leukocyte adhesion to retinal vasculature, early blood-retinal barrier breakdown, capillary nonperfusion, and endothelial cell death. We investigated the involvement of tumor necrosis factor α (TNF-α) in diabetes-related histopathological changes in two relevant rodent models. In short-term studies, Long-Evans rats with streptozotocin–induced diabetes were treated with or without the TNF-α inhibitor, etanercept. For long-term studies, tumor necrosis factor receptor I (TNF-RI)-deficient mice and TNF-RII-deficient mice, as well as C57/Bl6 wild-type mice, were fed 30% galactose for up to 20 months. The retinal histopathological alterations of hypergalactosemia were analyzed in trypsin digest preparations. Endothelial cell injury and apoptosis in rat retinas were evaluated by propidium iodide, TUNEL, CytoDeath staining, and DNA fragmentation ELISA. Caspase 3 and 8 activity was evaluated by immunoblotting and quantitative enzymatic activity assay. Etanercept suppressed caspase activation, retinal cell injury, and apoptosis in short-term diabetic rats. Pericyte and endothelial cell loss were also reduced in long-term hypergalactosemic mice. Long-term studies demonstrated that pericyte loss and endothelial cell loss were reduced in comparison to wild-type diabetic controls. Our study identifies an important role for TNF-α in the pathogenesis of signature diabetic retinopathy pathologies and demonstrates that etanercept can inhibit retinal cell death and long-term complication of diabetes. Taken together, our results suggest that etanercept could prove beneficial in preventing both early and late vascular diabetic complications.

This review highlights the role of three key immune pathways in the pathophysiology of major retinal degenerative diseases including diabetic retinopathy, age‐related macular degeneration, and rare retinal dystrophies. We first discuss the mechanisms how loss of retinal homeostasis evokes an unbalanced retinal immune reaction involving responses of local microglia and recruited macrophages, activity of the alternative complement system, and inflammasome assembly in the retinal pigment epithelium. Presenting these key mechanisms as complementary targets, we specifically emphasize the concept of immunomodulation as potential treatment strategy to prevent or delay vision loss. Promising molecules are ligands for phagocyte receptors, specific inhibitors of complement activation products, and inflammasome inhibitors. We comprehensively summarize the scientific evidence for this strategy from preclinical animal models, human ocular tissue analyses, and clinical trials evolving in the last few years.