Targeting Interleukin-6 Trans-signaling in Diabetic Retinopathy

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Project Summary Diabetic retinopathy (DR) is a sight-threatening neurovasculopathy, which is the leading cause of blindness in working-aged Americans. The new therapies to prevent retinal injury and enhance repair is a critical unmet need. The main focus of this proposal is to test a novel pharmacological compound sgp130Fc for the treatment of DR. Interleukin-6 (IL-6) is the major mediator of inflammation and increasing evidence suggests that the IL-6 pathway plays a prominent role in the pathogenesis of DR. Interestingly, even though the retinal endothelial cells lack membrane bound IL-6 receptor, IL-6 mediated signaling is observed in these cells. Studies have shown that IL-6/soluble IL-6R complex can bind to glycoprotein 130 (gp130) to initiate downstream signaling in cells that do not express the IL-6 receptor and this process is known as IL-6 trans-signaling. Current approaches to block IL-6 signaling inhibit both classical and trans-signaling pathways. Recent studies suggest that IL-6 trans-signaling is particularly important in regulating processes localized to the site of disease or infection and is crucially involved in inflammatory diseases. We hypothesize that inhibiting only the trans-signaling pathway of IL-6 will be superior to complete IL-6 blockade, because important physiologic functions of IL-6 will remain intact. This novel intervention strategy represents the first attempt to investigate the effects of selective IL-6 trans-signaling blockade in DR treatment. We have exciting preliminary data showing that inhibition of IL-6 trans-signaling significantly decreases the inflammatory response in human retinal endothelial cells and diabetic mice retina. In this proposal we will test the hypothesis that sgp130-Fc will slow disease progression and attenuate pathological ocular inflammation in diabetic retinopathy, when administered either prior to onset of DR or later at a clinically evident disease stage. In Aim-1, we will use in vitro approaches to determine the effects of IL-6 trans-signaling on endothelial-pericyte interaction, expression of adhesion and tight junctions molecules in the endothelial system, maintenance of barrier function, pericyte migration, ROS production, apoptosis and proliferation of endothelial cells and pericytes. In Aim-2, we will use the streptozotocin (STZ)-induced type-1 diabetes (T1D) mouse model to determine the effect of sgp130Fc drug treatment on the diabetes-induced retinal vascular pathology by conducting molecular, structural and functional studies in diabetic mice retinas. This project has the potential to provide a new therapeutic approach to treat retinal vascular pathology associated with diabetes.