MD2 blockade prevents modified LDL-induced retinal injury in diabetes by suppressing NADPH oxidase-4 interaction with Toll-like receptor-4

• Published in: Experimental & molecular medicine 2021, 53(0), , pp.1-14
• Main Authors: Chen, Huaicheng, Yan, Tao, Song, Zongming, Ying, Shilong, Wu, Beibei, Ju, Xin, Yang, Xi, Qu, Jia, Wu, Wencan, Zhang, Zongduan, Wang, Yi
• Format: Article
• Language: English
• Subjects: 13/1; 13/2; 13/95; 64/60; 692/699/1702/393; 692/699/2743/137/773; 82/80; 96/1; 96/31; Animals; Apoptosis; Biomedical and Life Sciences; Biomedicine; Blindness; Cell injury; Cholesterol, LDL - metabolism; Diabetes; Diabetes mellitus; Diabetic retinopathy; Diabetic Retinopathy - diagnosis; Diabetic Retinopathy - drug therapy; Diabetic Retinopathy - etiology; Diabetic Retinopathy - metabolism; Disease Models, Animal; Disease Susceptibility; Endoplasmic Reticulum Stress - drug effects; Ependymoglial Cells; Extravasation; Gene Silencing; Humans; Hyperglycemia; Inflammation; Lipids; Lipoproteins; Low density lipoprotein; Lymphocyte Antigen 96 - antagonists & inhibitors; Male; Medical Biochemistry; Mice; Models, Biological; Molecular Medicine; Mueller cells; NAD(P)H oxidase; NADPH Oxidase 4 - metabolism; NOX4 protein; Oxidative stress; Proteins; Reactive oxygen species; Reactive Oxygen Species - metabolism; Retina; Retinopathy; Risk factors; Signal transduction; Signal Transduction - drug effects; Stem Cells; Therapeutic targets; TLR4 protein; Toll-Like Receptor 4 - metabolism; Toll-like receptors; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-021-00607-w

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. Diabetes: Specific protein inhibitors could reduce blindness Blocking the activity of a protein involved in triggering inflammation and oxidative stress in the retina may reduce diabetes-induced visual impairment and blindness. Besides hyperglycemia, plasma lipids and lipoproteins have also been proposed as potential risk factors for diabetic retinopathy. However, the precise mechanisms controlling low-density lipoprotein-induced retinal damage are unclear. In experiments on mice, Yi Wang at Wenzhou Medical University in Wenzhou, China, and co-workers found that retinal injury caused by highly oxidized glycated-LDL is mediated by the myeloid differentiation protein 2 (MD2). Blocking MD2 with an inhibitor suppressed two key signaling pathways, reducing the production of reactive oxygen species and inflammatory signaling proteins in the retina. Further investigations are needed, but the team believe MD2 could be a vital therapeutic target for diabetic retinopathy.