Protective roles of the TIR/BB-loop mimetic AS-1 in alkali-induced corneal neovascularization by inhibiting ERK phosphorylation.
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.
['Liu|Yanqiu|Y|', 'Shu|Yishun|Y|', 'Yin|Li|L|', 'Xie|Tianhua|T|', 'Zou|Jian|J|', 'Zhan|Pengfei|P|', 'Wang|Yangningzhi|Y|', 'Wei|Tingting|T|', 'Zhu|Lingpeng|L|', 'Yang|Xusheng|X|', 'Wang|Wenjuan|W|', 'Cai|Jiping|J|', 'Li|Yuehua|Y|', 'Yao|Yong|Y|', 'Wang|Xiaolu|X|']
D020533:Angiogenesis Inhibitors D000818:Animals D015415:Biomarkers D015153:Blotting, Western D002057:Burns, Chemical D016510:Corneal Neovascularization D004195:Disease Models, Animal D019573:Epithelium, Corneal D048049:Extracellular Signal-Regulated MAP Kinases D005126:Eye Burns D005136:Eye Proteins D006801:Humans D047468:Immunoprecipitation D042583:Lymphangiogenesis D051379:Mice D008810:Mice, Inbred C57BL D010766:Phosphorylation D011759:Pyrrolidines D060888:Real-Time Polymerase Chain Reaction D012972:Sodium Hydroxide D014633:Valine
TIR/BB-Loop mimetic AS-1 Corneal neovascularization ERK phosphorylation