Sarah I Lindstrom1, Sigrun Sigurdardottir1, Thomas E Zapadka1, Jie Tang2, Haitao Liu2, Brooklyn E Taylor1, Dawn G Smith1, Chieh A Lee2, John DeAngelis3, Timothy S Kern4, Patricia R Taylor5. 1. Department of Ophthalmology and Visual Sciences, Case Western Reserve University, School of Medicine, Cleveland, OH, United States of America. 2. Department of Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, OH, United States of America. 3. James E. Van Zandt VA Medical Center, Altoona, PA, United States of America. 4. Department of Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, OH, United States of America; Louis Stokes VA Medical Center, Cleveland, OH, United States of America. 5. Department of Ophthalmology and Visual Sciences, Case Western Reserve University, School of Medicine, Cleveland, OH, United States of America; Louis Stokes VA Medical Center, Cleveland, OH, United States of America. Electronic address: patricia.r.taylor@case.edu.
Abstract
PURPOSE: Diabetes leads to progressive complications such as diabetic retinopathy, which is the leading cause of blindness within the working-age population worldwide. Interleukin (IL)-17A is a cytokine that promotes and progresses diabetes. The objective of this study was to determine the role of IL-17A in retinal capillary degeneration, and to identify the mechanism that induces retinal endothelial cell death. These are clinically meaningful abnormalities that characterize early-stage non-proliferative diabetic retinopathy. METHODS: Retinal capillary degeneration was examined in vivo using the streptozotocin (STZ) diabetes murine model. Diabetic-hyperglycemia was sustained for an 8-month period in wild type (C57BL/6) and IL-17A-/- mice to elucidate the role of IL-17A in retinal capillary degeneration. Further, ex vivo studies were performed in retinal endothelial cells to identify the IL-17A-dependent mechanism that induces cell death. RESULTS: It was determined that diabetes-induced retinal capillary degeneration was significantly lower in IL-17A-/- mice. Further, retinal endothelial cell death occurred through an IL-17A/IL-17R ➔ Act1/FADD signaling cascade, which caused caspase-mediated apoptosis. CONCLUSION: These are the first findings that establish a pathologic role for IL-17A in retinal capillary degeneration. Further, a novel IL-17A-dependent apoptotic mechanism was discovered, which identifies potential therapeutic targets for the early onset of diabetic retinopathy. Published by Elsevier Inc.
PURPOSE:Diabetes leads to progressive complications such as diabetic retinopathy, which is the leading cause of blindness within the working-age population worldwide. Interleukin (IL)-17A is a cytokine that promotes and progresses diabetes. The objective of this study was to determine the role of IL-17A in retinal capillary degeneration, and to identify the mechanism that induces retinal endothelial cell death. These are clinically meaningful abnormalities that characterize early-stage non-proliferative diabetic retinopathy. METHODS:Retinal capillary degeneration was examined in vivo using the streptozotocin (STZ) diabetesmurine model. Diabetic-hyperglycemia was sustained for an 8-month period in wild type (C57BL/6) and IL-17A-/- mice to elucidate the role of IL-17A in retinal capillary degeneration. Further, ex vivo studies were performed in retinal endothelial cells to identify the IL-17A-dependent mechanism that induces cell death. RESULTS: It was determined that diabetes-induced retinal capillary degeneration was significantly lower in IL-17A-/- mice. Further, retinal endothelial cell death occurred through an IL-17A/IL-17R ➔ Act1/FADD signaling cascade, which caused caspase-mediated apoptosis. CONCLUSION: These are the first findings that establish a pathologic role for IL-17A in retinal capillary degeneration. Further, a novel IL-17A-dependent apoptotic mechanism was discovered, which identifies potential therapeutic targets for the early onset of diabetic retinopathy. Published by Elsevier Inc.
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