Protective roles of the TIR/BB-loop mimetic AS-1 in alkali-induced corneal neovascularization by inhibiting ERK phosphorylation.

Abstract

Hydrocinnamoyl-L-valylpyrrolidine (AS-1), a synthetic low-molecule mimetic of myeloid differentiation primary response gene 88 (MyD88), inhibits inflammation by disrupting the interaction between the interleukin-1 receptor (IL-1R) and MyD88. Here, we describe the effects of AS-1 on injury-induced increases in inflammation and neovascularization in mouse corneas. Mice were administered a subconjunctival injection of 8 μL AS-1 diluent before or after corneal alkali burn, followed by evaluation of corneal resurfacing and corneal neovascularization (CNV) by slit-lamp biomicroscopy and clinical assessment. Corneal inflammation was assessed by whole-mount CD45+ immunofluorescence staining, and corneal hemangiogenesis and lymphangiogenesis following injury were evaluated by immunostaining for the vascular markers isolectin B4 (IB4) and the lymphatic vascularized marker lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), respectively. Additionally, corneal tissues were collected to determine the expression of 35 cytokines, and we detected activation of IL-1RI, MyD88, and mitogen-activated protein kinase (MAPK). The results showed that alkali conditions increased the number of CD45+ cells and expression of vascular endothelial growth factor (VEGF)-A, VEGF-C, and LYVE1 in corneas, with these levels decreased in the AS-1-treated group. Moreover, AS-1 effectively prevented alkali-induced cytokine production, blocked interactions between IL-1RI and MyD88, and inhibited MAPK activation post-alkali burn. These results indicated that AS-1 prevented alkali-induced corneal hemangiogenesis and lymphangiogenesis by blocking IL-1RI-MyD88 interaction, as well as extracellular signal-regulated kinase phosphorylation, and could be efficacious for the prevention and treatment of corneal alkali burn.

• Authors: Yanqiu Liu, Yishun Shu, Li Yin, Tianhua Xie, Jian Zou, Pengfei Zhan, Yangningzhi Wang, Tingting Wei, Lingpeng Zhu, Xusheng Yang, Wenjuan Wang, Jiping Cai, Yuehua Li, Yong Yao, Xiaolu Wang
• Journal: Experimental eye research (Exp Eye Res) Vol. 207 Pg. 108568 (06 2021) ISSN: 1096-0007 [Electronic] England
• PMID: 33839112 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Ltd. All rights reserved.

Chemical References

• Angiogenesis Inhibitors
• Biomarkers
• Eye Proteins
• Pyrrolidines
• hydrocinnamoyl-1-valyl pyrrolidine
• Sodium Hydroxide
• Extracellular Signal-Regulated MAP Kinases
• Valine

Topics

• Angiogenesis Inhibitors
• Animals
• Biomarkers (metabolism)
• Blotting, Western
• Burns, Chemical (enzymology, pathology, prevention & control)
• Corneal Neovascularization (enzymology, pathology, prevention & control)
• Disease Models, Animal
• Epithelium, Corneal (drug effects, metabolism)
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, metabolism)
• Eye Burns (chemically induced, enzymology, pathology)
• Eye Proteins (metabolism)
• Humans
• Immunoprecipitation
• Lymphangiogenesis (drug effects)
• Mice
• Mice, Inbred C57BL
• Phosphorylation
• Pyrrolidines (therapeutic use)
• Real-Time Polymerase Chain Reaction
• Sodium Hydroxide
• Valine (analogs & derivatives, therapeutic use)