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

Curr Eye Res. 2023 May;48(5):474-484. doi: 10.1080/02713683.2022.2164780. Epub 2023 Jan 9.

Abstract

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-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.

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.

Keywords: Age-related macular degeneration; chalcone analogs; inflammation; myeloid differentiation protein 2; oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Choroidal Neovascularization* / metabolism
  • Inflammation
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism
  • Signal Transduction / physiology
  • Toll-Like Receptor 4* / genetics
  • Toll-Like Receptor 4* / metabolism

Substances

  • NF-kappa B
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Ly96 protein, mouse