ArticleExperimental & molecular medicine2021
MD2 blockade prevents modified LDL-induced retinal injury in diabetes by suppressing NADPH oxidase-4 interaction with Toll-like receptor-4.
Article in Experimental & molecular medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 13 citations in OpenAlex.
- Breakthroughs in diabetic retinopathy diagnosis and treatment using preclinical research models: current progress and future directions.Annals of medicine · 2025Review
- Computational Identification and Anti-Inflammatory Evaluation of T19093 as a TLR4/MD2 Inhibitor.Current topics in medicinal chemistry · 2025Article
- Deep Immune and RNA Profiling Revealed Distinct Circulating CD163+ Monocytes in Diabetes-Related Complications.International journal of molecular sciences · 2024Article
- Analysis and validation of potential ICD-related biomarkers in development of myopia using machine learning.International ophthalmology · 2024Article
- Diabetic vascular diseases: molecular mechanisms and therapeutic strategies.Signal transduction and targeted therapy · 2023Review
- Immunohistochemical Localization of MD2, a Co-Receptor of TLR4, in the Adult Mouse Brain.ACS chemical neuroscience · 2023Article
- Toll-Like Receptor Signalling Pathways and the Pathogenesis of Retinal Diseases.Frontiers in ophthalmology · 2022Review
- Regulations of Retinal Inflammation: Focusing on Müller Glia.Frontiers in cell and developmental biology · 2022Review
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Modified LDL-induced inflammation and oxidative stress are involved in the pathogenesis of diabetic retinopathy. Recent studies have also shown that modified LDL activates Toll-like receptor 4 (TLR4) to mediate retinal injury. However, the mechanism by which modified LDL activates TLR4 and the potential role of the TLR4 coreceptor myeloid differentiation protein 2 (MD2) are not known. In this study, we inhibited MD2 with the chalcone derivatives L2H17 and L6H21 and showed that MD2 blockade protected retinal Müller cells against highly oxidized glycated-LDL (HOG-LDL)-induced oxidative stress, inflammation, and apoptosis. MD2 inhibition reduced oxidative stress by suppressing NADPH oxidase-4 (NOX4). Importantly, HOG-LDL activated TLR4 and increased the interaction between NOX4 and TLR4. MD2 was required for the activation of these pathways, as inhibiting MD2 prevented the association of NOX4 with TLR4 and reduced NOX4-mediated reactive oxygen species production and TLR4-mediated inflammatory factor production. Furthermore, treatment of diabetic mice with L2H17 significantly reduced LDL extravasation in the retina and prevented retinal dysfunction and apoptosis by suppressing the TLR4/MD2 pathway. Our findings provide evidence that MD2 plays a critical role in mediating modified LDL-induced cell injury in the retina and suggest that targeting MD2 may be a potential therapeutic strategy.
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