Evidence map›Paper›PMID 40654673›Full record

ArticlebioRxiv : the preprint server for biology2025

Lysyl oxidase promotes actin-dependent neutrophil activation and cytotoxicity in diabetes: Implications for diabetic retinopathy.

Mahesh Agarwal, Sathishkumar Chandrakumar, Irene Santiago Tierno, Emma M Lessieur, Zak R Bollinger, Timothy S Kern, Kaustabh Ghosh

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

7 authors.

Mahesh AgarwalDepartment of Ophthalmology, University of California, Los Angeles, CA, USA 90095.ORCID 0000-0002-0529-0196
Sathishkumar ChandrakumarDepartment of Ophthalmology, University of California, Los Angeles, CA, USA 90095.ORCID 0000-0003-2320-050X
Irene Santiago TiernoDepartment of Ophthalmology, University of California, Los Angeles, CA, USA 90095.ORCID 0009-0001-2368-2505
Emma M LessieurDepartment of Ophthalmology, Center for Translational Vision Research, University of California, Irvine, CA 92697.
Zak R BollingerDepartment of Ophthalmology, Center for Translational Vision Research, University of California, Irvine, CA 92697.
Timothy S KernDepartment of Ophthalmology, Center for Translational Vision Research, University of California, Irvine, CA 92697.ORCID 0000-0003-1188-0739
Kaustabh GhoshDepartment of Ophthalmology, University of California, Los Angeles, CA, USA 90095.ORCID 0000-0001-8185-9180

Funding

Novel therapies to inhibit Diabetic RetinopathyR24EY024864 · NEI · UNIVERSITY OF CALIFORNIA-IRVINE · PI KERN, TIMOTHY S · 2015 to 2019
$8.1M
NEI UCI Center Core Grant for Vision ResearchP30EY034070 · NEI · UNIVERSITY OF CALIFORNIA-IRVINE · PI Vladimir Jivkov Kefalov · 2022 to 2026
$3.7M
Role of Photoreceptors in the Pathogenesis of Diabetic RetinopathyR01EY022938 · NEI · UNIVERSITY OF CALIFORNIA-IRVINE · PI KERN, TIMOTHY S · 2013 to 2021
$3.7M
Role of Retinal Capillary Stiffness in Diabetic RetinopathyR01EY028242 · NEI · UNIVERSITY OF CALIFORNIA RIVERSIDE · PI GHOSH, KAUSTABH · 2017 to 2021
$1.9M
Neutrophil elastase and Gasdermin D in diabetic retinopathyR01EY033002 · NEI · UNIVERSITY OF CALIFORNIA-IRVINE · PI SKOWRONSKA-KRAWCZYK, DOROTA · 2021 to 2025
$1.9M
NEI NIH HHS P30 EY034070NEI NIH HHS R01 EY022938NEI NIH HHS R01 EY028242NEI NIH HHS R01 EY033002NEI NIH HHS R24 EY024864
6 · The paper itself

Abstract

Activated neutrophils contribute to retinal endothelial cell (EC) death and capillary degeneration associated with early diabetic retinopathy (DR). However, the factors and mechanisms driving neutrophil activation and cytotoxicity in diabetes remain insufficiently understood. Here we show that lysyl oxidase (LOX), a collagen crosslinking and matrix stiffening enzyme that increases retinal EC susceptibility to activated neutrophils, simultaneously activates neutrophils in its alternate soluble form. Specifically, treatment of diabetic mice with LOX inhibitor β-aminopropionitrile (BAPN) prevented the diabetes-induced increase in neutrophil activation (extracellular release of neutrophil elastase and superoxide) and cytotoxicity towards co-cultured mouse retinal ECs. Mouse neutrophils and differentiated (neutrophil-like) human HL-60 cells treated with recombinant LOX alone exhibited similar activation and cytotoxicity. Mechanistically, this LOX-induced neutrophil activation was associated with biphasic F-actin remodeling, with the initial and rapid (<15 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 towards co-cultured retinal ECs. Finally, we show that this biphasic F-actin remodeling is essential for LOX-induced membrane clustering of azurophilic granule marker CD63 and NADPH organizer p47 that are associated with extracellular release of neutrophil elastase and superoxide, respectively. By revealing a causal and previously unrecognized 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.

Indexed as

ActinDiabetesLeukocytesLysyl oxidaseNeutrophil elastaseRetinal endothelial cells

Identifiers

PMID40654673
PMCPMC12248121

What OpenQuestion holds

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.