PMID- 36591949 OWN - NLM STAT- MEDLINE DCOM- 20230420 LR - 20230420 IS - 1460-2202 (Electronic) IS - 0271-3683 (Linking) VI - 48 IP - 5 DP - 2023 May TI - MD2 Inhibits Choroidal Neovascularization via Antagonizing TLR4/MD2 Mediated Signaling Pathway. PG - 474-484 LID - 10.1080/02713683.2022.2164780 [doi] AB - PURPOSE: 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). METHODS: 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. RESULTS: 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-alpha, 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-kappaB (NF-kappaB) activation. CONCLUSIONS: 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. FAU - Wu, Qi AU - Wu Q AD - School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China. AD - State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health P. R. China and Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, China. FAU - Chen, Zhang AU - Chen Z AD - The Second Affiliated Hospital, Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China. FAU - Wu, Chenxin AU - Wu C AD - School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China. AD - State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health P. R. China and Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, China. FAU - Zhang, Lingxi AU - Zhang L AD - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China. FAU - Wu, Yuyang AU - Wu Y AD - School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China. AD - State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health P. R. China and Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, China. FAU - Liu, Xiyuan AU - Liu X AD - School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China. AD - State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health P. R. China and Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, China. FAU - Wang, Yi AU - Wang Y AD - Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China. FAU - Zhang, Zongduan AU - Zhang Z AUID- ORCID: 0000-0002-9509-231X AD - School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou, China. AD - State Key Laboratory Cultivation Base and Key Laboratory of Vision Science, Ministry of Health P. R. China and Zhejiang Provincial Key Laboratory of Ophthalmology and Optometry, Wenzhou, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230109 PL - England TA - Curr Eye Res JT - Current eye research JID - 8104312 RN - 0 (NF-kappa B) RN - 0 (Tlr4 protein, mouse) RN - 0 (Toll-Like Receptor 4) RN - 0 (Ly96 protein, mouse) SB - IM MH - Animals MH - Mice MH - *Choroidal Neovascularization/metabolism MH - Inflammation MH - Mice, Inbred C57BL MH - NF-kappa B/metabolism MH - Signal Transduction/physiology MH - *Toll-Like Receptor 4/genetics/metabolism OTO - NOTNLM OT - Age-related macular degeneration OT - chalcone analogs OT - inflammation OT - myeloid differentiation protein 2 OT - oxidative stress EDAT- 2023/01/03 06:00 MHDA- 2023/04/19 06:41 CRDT- 2023/01/02 07:22 PHST- 2023/04/19 06:41 [medline] PHST- 2023/01/03 06:00 [pubmed] PHST- 2023/01/02 07:22 [entrez] AID - 10.1080/02713683.2022.2164780 [doi] PST - ppublish SO - Curr Eye Res. 2023 May;48(5):474-484. doi: 10.1080/02713683.2022.2164780. Epub 2023 Jan 9.