This study investigated the hypothesis that diabetes-induced hyperglycemia promotes retinal inflammation by augmenting translation of the immune costimulatory molecule CD40. In response to diabetes, Müller glia initiate retinal inflammation via activation of CD40. CD40 activation in Müller glia leads to ATP release, stimulation of P2X7 purinergic receptors on microglia/macrophages, and their subsequent release of inflammatory cytokines. Increased CD40 expression is a common feature of inflammatory diseases driven by CD40. Indeed, CD40 protein expression is elevated in Müller glia of diabetic mice, yet the mechanisms responsible for this increase have not been fully explored. In microglia/macrophages, inflammatory cytokines enhance CD40 gene transcription via cis-elements in the CD40 promoter. However, cytokine-mediated CD40 transcriptional upregulation is not sufficient to explain a model wherein retinal inflammation is initiated by CD40 expression in Müller glia. A recent genome-wide functional screening revealed that the untranslated region of the mRNA encoding CD40 was capable of promoting translation independent of the mRNA m7GTP cap. Our laboratory has previously demonstrated that diabetes-induced hyperglycemia promotes O-GlcNAcylation of the translational repressor 4E-BP1, leading to enhanced cap-independent mRNA translation. In the present study, in vivo translation of the CD40 mRNA was enhanced in Müller glia of STZ-diabetic RiboTag mice concomitant with increased protein O-GlcNAcylation. Enhanced O-GlcNAcylation was sufficient to promote CD40 mRNA translation in both retina and cells in culture, and O-GlcNAcylation-induced CD40 mRNA translation was ablated by 4E-BP deletion. In the retina of diabetic 4E-BP-deficient mice, CD40 translation and retinal pathology were normalized. Thus, therapeutic approaches targeting diabetes-induced defects in mRNA translation may be beneficial for preventing diabetic retinopathy progression.
S.K. Dierschke: None. A. Toro: None. W.P. Miller: None. M.D. Dennis: None.
American Diabetes Association/Pathway to Stop Diabetes (1-14-INI-04 to M.D.D.)