MD2 Inhibits Choroidal Neovascularization via Antagonizing TLR4/MD2 Mediated Signaling Pathway.

Qi Wu, Zhang Chen, Chenxin Wu, Lingxi Zhang, Yuyang Wu, Xiyuan Liu, Yi Wang, Zongduan Zhang

Current eye research 2023 May

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To explore the pathological mechanism of Toll-like receptor 4 (TLR4) mediating neovascular age-related macular degeneration (nAMD) and the potential role of the TLR4 coreceptor myeloid differentiation protein 2 (MD2). In the study, we inhibited MD2 with the chalcone derivative L2H17 and we utilized a laser-induced choroidal neovascularization (CNV) mouse model and Tert-butyl hydroperoxide (TBHP)-challenged rhesus choroid-retinal endothelial (RF/6A) cells to assess the effect of MD2 blockade on CNV. Inhibiting MD2 with L2H17 reduced angiogenesis in CNV mice, and significantly protected against retinal dysfunction. In retina and choroid/retinal pigment epithelium (RPE) tissues, L2H17 reduced phospho-ERK, phospho-P65 but not phospho-P38, phospho-JNK, and reduced the transcriptional levels of IL-6, TNF-α, ICAM-1 but not VCAM-1. L2H17 could protect RF/6A against TBHP-induced inflammation, oxidative stress, and apoptosis, via inhibiting the TLR4/MD2 signaling pathway and the following downstream mitogen-activated protein kinase (MAPK) and nuclear transcription factor-κB (NF-κB) activation. Inhibiting MD2 with L2H17 significantly reduced CNV, suppressed inflammation, and oxidative stress by antagonizing TLR4/MD2 pathway in an MD2-dependent manner. MD2 may be a potential therapeutic target and L2H17 may offer an alternative treatment strategy for nAMD.

Citation

Qi Wu, Zhang Chen, Chenxin Wu, Lingxi Zhang, Yuyang Wu, Xiyuan Liu, Yi Wang, Zongduan Zhang. MD2 Inhibits Choroidal Neovascularization via Antagonizing TLR4/MD2 Mediated Signaling Pathway. Current eye research. 2023 May;48(5):474-484