{"doi":"10.1167/iovs.65.3.34","title":"NLRP3 Inflammasome Priming in the Retina of Diabetic Mice Requires REDD1-Dependent Activation of GSK3β","abstract":"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 Müller 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 Müller cell cultures, NLRP3 and interleukin-1β (IL-1β) 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 Müller cells exposed to hyperglycemic conditions and reduced IL-1β release. REDD1 promoted nuclear factor κB signaling in cells exposed to hyperglycemic conditions, which was necessary for an increase in NLRP3. Expression of a constitutively active GSK3β 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. Müller 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 GSK3β in NLRP3 inflammasome transcriptional priming and in the production of IL-1β by Müller glia in response to diabetes.","journal":"Investigative Ophthalmology & Visual Science","year":2024,"id":425934,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9638,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":452862,"name":"Siddharth Sunilkumar","orcid":"0000-0003-3271-932X","position":1,"is_corresponding":false},{"id":890383,"name":"Sandeep Subrahmanian","orcid":"0000-0001-6462-8428","position":2,"is_corresponding":false},{"id":940645,"name":"Esma I. Yerlikaya","orcid":null,"position":3,"is_corresponding":false},{"id":453863,"name":"Allyson L. Toro","orcid":null,"position":4,"is_corresponding":false},{"id":513604,"name":"Ashley M. VanCleave","orcid":"0000-0002-2033-1822","position":5,"is_corresponding":false},{"id":452863,"name":"Shaunaci A. Stevens","orcid":"0000-0001-6904-1618","position":6,"is_corresponding":false},{"id":423749,"name":"Alistair J. Barber","orcid":"0000-0003-4235-2293","position":7,"is_corresponding":false},{"id":1224756,"name":"Jeffery M. Sundstrom","orcid":null,"position":8,"is_corresponding":false},{"id":452865,"name":"Michael D. Dennis","orcid":"0000-0002-0645-6864","position":9,"is_corresponding":false},{"id":906283,"name":"Christopher M. McCurry","orcid":"0000-0003-0657-2547","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T01:58:32.160975Z","pmid":"38546584","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}