Microglia-Derived Interleukin-6 Increases Retinal Endothelial Cell Permeability Through Stat3 Activation In Diabetic Retinopathy

Diabetic retinopathy (DR) accompanies an inflammatory response associated with an increase in inflammatory cytokines. Among cytokines elevated in the diabetic retina, the mechanism by which IL-6 induces DR pathologies, more specifically endothelial permeability, is not well understood. Thus, we focused on the cellular source of the elevated IL-6 in high glucose condition and the molecular mechanism by which IL-6 impairs endothelial tight junctions. In the present study, we found that the expression of IL-6 and TNF-α was elevated in the streptozotocin-induced diabetic retina and that IL-6, but not TNF-α, expression was increased in microglia exposed to high glucose condition in vitro. Interestingly, in co-culture condition with microglia and endothelial cell, microglia-derived IL-6 increased retinal endothelial permeability, which was exaggerated by high glucose exposure. We demonstrated that the IL-6 activated STAT3, through which led to the reduced expression of tight junction protein ZO-1 and occludin. Taken together, we propose that IL-6-induced STAT3 activation is important for the induction of endothelial permeability through the reduction of ZO-1 and occludin levels in retinal endothelial cells. In addition, microglia-derived IL-6 and IL-6/STAT3 signaling could be a therapeutic target to prevent the DR pathology.