NLRP3 Inflammasome Priming in the Retina of Diabetic Mice Requires REDD1-Dependent Activation of GSK3β

PURPOSE. Inflammasome activation has been implicated in the development of retinal complications caused by diabetes. This study was designed to identify signaling events that promote retinal NOD-, LRR-, and pyrin domain -containing protein 3 (NLRP3) inflammasome activation in response to diabetes. METHODS. Diabetes was induced in mice by streptozotocin administration. Retinas were examined after 16 weeks of diabetes. Human MIO-M1 M & uuml;ller cells were exposed to hyperglycemic culture conditions. Genetic and pharmacological interventions were used to interrogate signaling pathways. Visual function was assessed in mice using a virtual optomotor system. RESULTS. In the retina of diabetic mice and in M & uuml;ller cell cultures, NLRP3 and interleukin-1/3 (IL -1/3) were increased in response to hyperglycemic conditions and the stress response protein Regulated in Development and DNA damage 1 (REDD1) was required for the effect. REDD1 deletion prevented caspase-1 activation in M & uuml;ller cells exposed to hyperglycemic conditions and reduced IL -1/3 release. REDD1 promoted nuclear factor KB signaling in cells exposed to hyperglycemic conditions, which was necessary for an increase in NLRP3. Expression of a constitutively active GSK3/3 variant restored NLRP3 expression in REDD1-deficient cells exposed to hyperglycemic conditions. GSK3 activity was necessary for increased NLRP3 expression in the retina of diabetic mice and in cells exposed to hyperglycemic conditions. M & uuml;ller glia-specific REDD1 deletion prevented increased retinal NLRP3 levels and deficits in contrast sensitivity in diabetic mice. CONCLUSIONS. The data support a role for REDD1-dependent activation of GSK3/3 in NLRP3 inflammasome transcriptional priming and in the production of IL -1/3 by M & uuml;ller glia in response to diabetes.