{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T16:58:36Z","timestamp":1778691516543,"version":"3.51.4"},"reference-count":0,"publisher":"American Diabetes Association","license":[{"start":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T00:00:00Z","timestamp":1740009600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:p>The unfolded protein response (UPR) drives events that promote diabetic retinopathy including VEGF upregulation in M\u00fcller cells. How UPR is activated in vivo in the diabetic retina is not well understood. CD40 is required for development of diabetic retinopathy but whether CD40 mediates activation of UPR sensors is unknown. CD40 ligation in M\u00fcller cells caused phospholipase C\u03b31 (PLC\u03b31)-dependent activation of UPR sensors (PERK, IRE1\u03b1 and ATF6\u03b1), and VEGF production dependent on PLC\u03b31 and UPR sensors. Diabetic Cd40-\/- mice did not exhibit UPR activation and VEGF upregulation in the retina. These responses were restored in diabetic Cd40-\/- mice rescued to express WT CD40 in M\u00fcller cells but not in mice rescued to express a CD40 mutant unable to recruit TRAF2,3. Intravitreal administration of a cell-permeable CD40-TRAF2,3 disrupting peptide reduced UPR activation, VEGF upregulation and vascular leakage in diabetic mice. CD40 and TRAF2 in M\u00fcller cells from patients with diabetic retinopathy co-localized with activated UPR sensors and VEGF. Our studies indicate that CD40 (via TRAF2,3 signaling) is an inducer of UPR activation that triggers VEGF production in M\u00fcller cells. This work uncovered inhibition of CD40-TRAF2,3 signaling as a potential approach to impair UPR activation, VEGF upregulation and vascular leakage in diabetic retinopathy.<\/jats:p>","DOI":"10.2337\/db23-0538","type":"journal-article","created":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T15:55:11Z","timestamp":1740066911000},"update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":3,"title":["CD40 INDUCES UNFOLDED PROTEIN RESPONSE, UPREGULATION OF VEGF AND VASCULAR LEAKAGE IN DIABETIC RETINOPATHY"],"prefix":"10.2337","author":[{"given":"Sarah","family":"Vos","sequence":"first","affiliation":[{"name":"1Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, OH"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jose-Andres C.","family":"Portillo","sequence":"additional","affiliation":[{"name":"1Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, OH"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alyssa","family":"Hubal","sequence":"additional","affiliation":[{"name":"1Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, OH"},{"name":"3Department of Pathology, Case Western Reserve University, Cleveland, OH"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reena","family":"Bapputty","sequence":"additional","affiliation":[{"name":"2Department of Pediatrics, Case Western Reserve University, Cleveland, OH"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amelia","family":"Pfaff","sequence":"additional","affiliation":[{"name":"1Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, OH"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel","family":"Aaron","sequence":"additional","affiliation":[{"name":"1Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, OH"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Weng","sequence":"additional","affiliation":[{"name":"1Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, OH"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Da","family":"Sun","sequence":"additional","affiliation":[{"name":"4Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zheng-Rong","family":"Lu","sequence":"additional","affiliation":[{"name":"4Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin-Sang","family":"Yu","sequence":"additional","affiliation":[{"name":"1Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, OH"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos S.","family":"Subauste","sequence":"additional","affiliation":[{"name":"1Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, OH"},{"name":"3Department of Pathology, Case Western Reserve University, Cleveland, OH"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1167","published-online":{"date-parts":[[2025,2,20]]},"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/doi\/10.2337\/db23-0538\/800199\/db230538.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/doi\/10.2337\/db23-0538\/800199\/db230538.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T15:55:11Z","timestamp":1740066911000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/doi\/10.2337\/db23-0538\/157922\/CD40-INDUCES-UNFOLDED-PROTEIN-RESPONSE"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,20]]},"references-count":0,"URL":"https:\/\/doi.org\/10.2337\/db23-0538","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,20]]},"article-number":"db230538"}}