Sunilkumar S, Toro AL, McCurry CM, VanCleave AM, Stevens SA, Miller WP, Kimball SR, Dennis MD

Inflammation contributes to the progression of retinal pathology caused by diabetes. Here, we investigated a role for the stress response protein regulated in development and DNA damage response 1 (REDD1) in the development of retinal inflammation. Increased REDD1 expression was observed in the retina of mice after 16-weeks of streptozotocin ...

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(STZ)-induced diabetes, and REDD1 was essential for diabetes-induced pro-inflammatory cytokine expression. In human retinal MIO-M1 Mueller cell cultures, REDD1 deletion prevented increased pro-inflammatory cytokine expression in response to hyperglycemic conditions. REDD1 deletion promoted nuclear factor erythroid-2-related factor 2 (Nrf2) hyperactivation; however, Nrf2 was not required for reduced inflammatory cytokine expression in REDD1-deficient cells. Rather, REDD1 enhanced inflammatory cytokine expression by promoting activation of nuclear transcription factor ?B (NF-?B). In WT cells exposed to tumor necrosis factor ? (TNF?), inflammatory cytokine expression was increased in coordination with activating transcription factor 4 (ATF4)-dependent REDD1 expression and sustained activation of NF-?B. In both Mueller cell cultures exposed to TNF? and in the retina of STZ-diabetic mice, REDD1 deletion promoted inhibitor of ?B (I?B) expression and reduced NF-?B DNA-binding activity. We found that REDD1 acted upstream of I?B by enhancing both K63-ubiquitination and auto-phosphorylation of I?B kinase complex. In contrast with STZ-diabetic REDD1+/+ mice, I?B kinase complex autophosphorylation and macrophage infiltration were not observed in the retina of STZ-diabetic REDD1-/- mice. The findings provide new insight into how diabetes promotes retinal inflammation and support a model wherein REDD1 sustains activation of canonical NF-?B signaling.

Date: Dec. 01, 2022

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