MOLECULAR MECHANISMS OF INTERLEUKIN-6 TRANS-SIGNALING MEDIATED EFFECTS ON ENDOTHELIAL PERMEABILITY, MÜLLER GLIA DYSFUNCTION, AND VITREOUS PROTEOMIC ALTERATIONS IN DIABETIC RETINOPATHY

Abstract

Recent studies in our lab have demonstrated that interleukin 6 (IL-6) signaling through its soluble receptor (IL-6 “trans-signaling”) plays a role in the pathogenesis of diabetic retinopathy (DR). The major goals of this project are to expand upon this knowledge by evaluating the effects of trans-signaling on retinal endothelial gene expression and permeability, Müller glia mitochondrial dysfunction, and the murine vitreous proteome. This study demonstrates that (i) trans-signaling significantly upregulates genes related to inflammation and leukocyte recruitment in retinal endothelial cells, and (ii) that the changes to endothelial permeability induced by IL-6 trans-signaling are partially mediated by less of -catenin expression. It also demonstrates that (iii) IL-6 trans-signaling induces Müller glia mitochondrial dysfunction and apoptosis in a glucose-dependent manner, and (iv) that inhibition of IL-6 trans-signaling in a mouse model of DR prevents diabetes-induced alterations to the vitreous humor proteome. Together, these data emphasize the importance of IL-6 trans-signaling in DR pathology and its potential as a novel therapeutic target.