{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:20:56Z","timestamp":1787311256640,"version":"build-2736575974"},"reference-count":47,"publisher":"American Diabetes Association","issue":"1","license":[{"start":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T00:00:00Z","timestamp":1762214400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/content\/license"}],"funder":[{"name":"Department of Ophthalmology at the University of California, Los Angeles","award":["Unrestricted Grants"],"award-info":[{"award-number":["Unrestricted Grants"]}]},{"name":"Gavin Herbert Eye Institute at the University of California, Irvine.","award":["Unrestricted Grants"],"award-info":[{"award-number":["Unrestricted Grants"]}]},{"DOI":"10.13039\/100023885","name":"All of Us Research Program","doi-asserted-by":"publisher","award":["EY022938-S1"],"award-info":[{"award-number":["EY022938-S1"]}],"id":[{"id":"10.13039\/100023885","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100023885","name":"All of Us Research Program","doi-asserted-by":"publisher","award":["R01EY022938"],"award-info":[{"award-number":["R01EY022938"]}],"id":[{"id":"10.13039\/100023885","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100023885","name":"All of Us Research Program","doi-asserted-by":"publisher","award":["R01EY028242"],"award-info":[{"award-number":["R01EY028242"]}],"id":[{"id":"10.13039\/100023885","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100023885","name":"All of Us Research Program","doi-asserted-by":"publisher","award":["R01EY033002"],"award-info":[{"award-number":["R01EY033002"]}],"id":[{"id":"10.13039\/100023885","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100023885","name":"All of Us Research Program","doi-asserted-by":"publisher","award":["R24EY024864"],"award-info":[{"award-number":["R24EY024864"]}],"id":[{"id":"10.13039\/100023885","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Eye Institute core grant to Center for Translational Vision Research at the University of California, Irvine","award":["P30EY034070-01"],"award-info":[{"award-number":["P30EY034070-01"]}]},{"DOI":"10.13039\/100000888","name":"W. M. Keck Foundation","doi-asserted-by":"publisher","award":["Stephen Ryan Initiative for Macular Research (RIMR"],"award-info":[{"award-number":["Stephen Ryan Initiative for Macular Research (RIMR"]}],"id":[{"id":"10.13039\/100000888","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,1,1]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>Activated neutrophils contribute to retinal endothelial cell (EC) death and capillary degeneration associated with early diabetic retinopathy (DR), a major vision-threatening complication of diabetes. However, the factors and mechanisms driving neutrophil activation and cytotoxicity in diabetes remain insufficiently understood. Here, we show that lysyl oxidase (LOX), a matrix cross-linking and stiffening enzyme that increases retinal EC susceptibility to activated neutrophils, simultaneously activates neutrophils in its soluble form. Specifically, treatment of diabetic mice with LOX inhibitor \u03b2-aminopropionitrile (BAPN) prevented the diabetes-induced increase in neutrophil activation (extracellular release of neutrophil elastase and superoxide) and cytotoxicity toward cocultured mouse retinal ECs. Mouse neutrophils and differentiated (neutrophil-like) human HL-60 cells treated with recombinant LOX alone exhibited significant activation and cytotoxicity. Mechanistically, this LOX-induced neutrophil activation was associated with biphasic F-actin remodeling, with the initial and rapid (\u223c10 min) F-actin depolymerization followed by a significant increase in F-actin polymerization and polarization. Preventing the initial F-actin depolymerization blocked LOX-induced neutrophil activation and cytotoxicity toward cocultured retinal ECs. Finally, this biphasic F-actin remodeling was found to be essential for LOX-induced membrane aggregation of azurophilic granule marker CD63 and NADPH organizer p47phox, which are associated with extracellular release of neutrophil elastase and superoxide, respectively. By revealing a previously unrecognized causal link between LOX and actin-dependent neutrophil activation in diabetes, these findings provide fresh mechanistic insights into the proinflammatory role of LOX in early DR that goes beyond its canonical matrix-stiffening effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                    <jats:p>Activated neutrophils kill retinal endothelial cells (ECs) in early diabetic retinopathy, but how neutrophils become activated in diabetes is not well understood. We found that lysyl oxidase (LOX), whose matrix-localized form activates retinal ECs, can also directly activate neutrophils in its soluble form. LOX-induced release of neutrophil elastase and superoxide is mediated by actin remodeling and membrane aggregation of azurophilic granules. The dual ability of LOX to activate neutrophils (in its soluble form) and retinal ECs (in its matrix-localized form) implicates it as a key proinflammatory target for early diabetic retinopathy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db25-0541","type":"journal-article","created":{"date-parts":[[2025,11,4]],"date-time":"2025-11-04T20:46:46Z","timestamp":1762289206000},"page":"166-179","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":1,"title":["Lysyl Oxidase Promotes Actin-Dependent Neutrophil Activation and Cytotoxicity Toward Retinal Endothelial Cells in Diabetes"],"prefix":"10.2337","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0529-0196","authenticated-orcid":false,"given":"Mahesh","family":"Agarwal","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, University of California 1 , Los Angeles, Los Angeles, CA"},{"name":"Doheny Eye Institute 2 , Pasadena, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2320-050X","authenticated-orcid":false,"given":"Sathishkumar","family":"Chandrakumar","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of California 1 , Los Angeles, Los Angeles, CA"},{"name":"Doheny Eye Institute 2 , Pasadena, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Santiago Tierno","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of California 1 , Los Angeles, Los Angeles, CA"},{"name":"Doheny Eye Institute 2 , Pasadena, CA"},{"name":"Molecular, Cellular, and Integrative Physiology Interdepartmental PhD Program, University of California 3 , Los Angeles, Los Angeles, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9120-0291","authenticated-orcid":false,"given":"Emma M.","family":"Lessieur","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Center for Translational Vision Research, University of California 4 , Irvine, Irvine, CA"},{"name":"Gavin Herbert Eye Institute, University of California 5 , Irvine, Irvine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zak R.","family":"Bollinger","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Center for Translational Vision Research, University of California 4 , Irvine, Irvine, CA"},{"name":"Gavin Herbert Eye Institute, University of California 5 , Irvine, Irvine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy S.","family":"Kern","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Center for Translational Vision Research, University of California 4 , Irvine, Irvine, CA"},{"name":"Gavin Herbert Eye Institute, University of California 5 , Irvine, Irvine, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8185-9180","authenticated-orcid":false,"given":"Kaustabh","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of California 1 , Los Angeles, Los Angeles, CA"},{"name":"Doheny Eye Institute 2 , Pasadena, CA"},{"name":"Molecular, Cellular, and Integrative Physiology Interdepartmental PhD Program, University of California 3 , Los Angeles, Los Angeles, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2025,11,4]]},"reference":[{"key":"2026061115280086700_B1","doi-asserted-by":"crossref","first-page":"e93751","DOI":"10.1172\/jci.insight.93751","article-title":"Diabetic retinopathy: current understanding, mechanisms, and treatment strategies","volume":"2","author":"Duh","year":"2017","journal-title":"JCI 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