Diabetes upregulates the stress response protein Regulated in Development and DNA damage 1 (REDD1) in retinal Müller glia, which contributes to the development of gliosis, neurodegeneration, and impaired visual function.  In the last decade, independent investigations have demonstrated that inflammation contributes to the progression of retinal pathology caused by diabetes. We observed that chronic REDD1 expression in Müller glia sustains canonical nuclear factor kappa B (NF-κB) mediated proinflammatory signaling and immune cell infiltration in retina of diabetic mice. 

In diabetogenic conditions, REDD1 is required for activation of the serine/threonine protein kinase Glycogen synthase kinase-3 beta (GSK-3β) that plays a role in many biological processes including inflammation.  We demonstrated that REDD1-dependent GSK3 activity was necessary for increased expression of the proinflammatory chemokines and inflammatory immune cell infiltration into the inner retinal of diabetic mice. Notably, we delineated the role of REDD1-GSK3 signaling in the canonical NF-κB cascade activation showing that GSK3 activity is required for phosphorylation of the regulatory subunit of the upstream inhibitory κB kinase (NEMO).

Inflammasome activation has been implicated in the development of retinal complications caused by diabetes.  Among inflammasomes, the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is best known, in part owing to its unique sensitivity to a range of stimuli that impact cellular homeostasis. NLRP3 inflammasome activity is controlled by a two-step process that involves the (1) priming and (2) activation of the NLRP3 inflammasome complex. Under diabetogenic conditions, increased REDD1-GSK3 signaling in Müller glia  is required for NLRP3 inflammasome priming.