Protective roles of the TIR/BB-loop mimetic AS-1 in alkali-induced corneal neovascularization by inhibiting ERK phosphorylation. (June 2021)

• Record Type: Journal Article
• Authors: Liu, Yanqiu; Shu, Yishun; Yin, Li; Xie, Tianhua; Zou, Jian; Zhan, Pengfei; Wang, Yangningzhi; Wei, Tingting; Zhu, Lingpeng; Yang, Xusheng; Wang, Wenjuan; Cai, Jiping; Li, Yuehua; Yao, Yong; Wang, Xiaolu
• Is Part Of: Experimental eye research. Volume 207(2021)
• Publication Date: 2021-06
• Subjects: TIR/BB-Loop mimetic AS-1 -- Corneal neovascularization -- ERK phosphorylation; Ophthalmology -- Periodicals; Eye -- Periodicals; Œil -- Périodiques; Ophthalmology; Periodicals; Electronic journals; 612.8405
• DOI: 10.1016/j.exer.2021.108568
• Languages: English
• ISSNs: 0014-4835

Abstract

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. Highlights: AS-1 inhibits CNV and decreases inflammatory cell infiltration in vitro and in vivo . AS-1 directly mediates MyD88–IL-1RI interaction and subsequent ERK activation. The results identified IL-1RI signaling in the progression of alkali-induced CNV. AS-1 is a therapeutic target for preventing hemangiogenesis and lymphangiogenesis.