Il-1 Beta Is Upregulated In The Diabetic Retina And Retinal Vessels: Cell-Specific Effect Of High Glucose And Il-1 Beta Autostimulation

Many molecular and cellular abnormalities detected in the diabetic retina support a role for IL-1 beta-driven neuroinflammation in the pathogenesis of diabetic retinopathy. IL-1 beta is well known for its role in the induction and, through autostimulation, amplification of neuroinflammation. Upregulation of IL-1 beta has been consistently detected in the diabetic retina; however, the mechanisms and cellular source of IL-1 beta overexpression are poorly understood. The aim of this study was to investigate the effect of high glucose and IL-1 beta itself on IL-1 beta expression in microglial, macroglial (astrocytes and Muller cells) and retinal vascular endothelial cells; and to study the effect of diabetes on the expression of IL-1 beta in isolated retinal vessels and on the temporal pattern of IL-1 beta upregulation and glial reactivity in the retina of streptozotocin-diabetic rats. IL-1 beta was quantified by RealTime RT-PCR and ELISA, glial fibrillar acidic protein, alpha 2-macroglobulin, and ceruloplasmin by immunoblotting. We found that high glucose induced a 3-fold increase of IL-1 beta expression in retinal endothelial cells but not in macroglia and microglia. IL-1 beta induced its own synthesis in endothelial and macroglial cells but not in microglia. In retinal endothelial cells, the high glucose-induced IL-1 beta overexpression was prevented by calphostin C, a protein kinase C inhibitor. The retinal vessels of diabetic rats showed increased IL-1 beta expression as compared to non-diabetic rats. Retinal expression of IL-1 beta increased early after the induction of diabetes, continued to increase with progression of the disease, and was temporally associated with upregulation of markers of glial activation. These findings point to hyperglycemia as the trigger and to the endothelium as the origin of the initial retinal upregulation of IL-1 beta in diabetes; and to IL-1 beta itself, via autostimulation in endothelial and macroglial cells, as the mechanism of sustained IL-1 beta overexpression. Interrupting the vicious circle triggered by IL-1 beta autostimulation could limit the progression of diabetic retinopathy.