State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
Biomolecules. 2020 Jan 31;10(2):210. doi: 10.3390/biom10020210.
Inflammation-induced angiogenesis is closely related to many diseases and has been regarded as a therapeutic target. Caspase-8 has attracted increasing attention for its immune properties and therapeutic potential in inflammatory disorders. The aim of our study is to investigate the clinical application of pharmacological inhibition of caspase-8 and the underlying molecular mechanisms in inflammation-induced angiogenesis in the cornea. A model of alkali burn (AB)-induced corneal neovascularization (CNV) in C57BL/6 wild-type (WT) mice and toll-like receptor 4 knockout (Tlr4) mice was used. We found that AB increased caspase-8 activity and the pharmacological inhibition of caspase-8 exerted substantial inhibitory effects on CNV, with consistent decreases in caspase-8 activity, inflammatory cell infiltration, macrophage recruitment and activation, VEGF-A, TNF-α, IL-1β, MIP-1, and MCP-1 expression in the cornea. In vitro, caspase-8 mediated TLR4-dependent chemokines and VEGF-A production by macrophages. The TLR4 knockout significantly alleviated CNV, suppressed caspase-8 activity and downregulated expression of inflammatory cytokines and chemokines after AB. Taken together, these findings provide the first demonstration that the pharmacological inhibition of caspase-8 suppresses inflammation-induced angiogenesis and support the use of a pharmacological caspase-8 inhibitor as a novel clinical treatment for CNV and other angiogenic disorders.
炎症诱导的血管生成与许多疾病密切相关，已被视为治疗靶点。Caspase-8 因其免疫特性和在炎症性疾病中的治疗潜力而引起了越来越多的关注。我们的研究旨在探讨药理学抑制 Caspase-8 在炎症诱导的角膜血管生成中的临床应用及其潜在的分子机制。我们使用 C57BL/6 野生型（WT）小鼠和 Toll 样受体 4 敲除（Tlr4）小鼠的碱烧伤（AB）诱导角膜新生血管（CNV）模型。我们发现 AB 增加了 Caspase-8 的活性，而 Caspase-8 的药理学抑制对 CNV 具有显著的抑制作用，导致 Caspase-8 活性、炎症细胞浸润、巨噬细胞募集和激活、VEGF-A、TNF-α、IL-1β、MIP-1 和 MCP-1 在角膜中的表达一致下降。在体外，Caspase-8 介导巨噬细胞中 TLR4 依赖性趋化因子和 VEGF-A 的产生。TLR4 敲除小鼠明显减轻 CNV，抑制 AB 后 Caspase-8 活性和下调炎症细胞因子和趋化因子的表达。综上所述，这些发现首次证明了药理学抑制 Caspase-8 可抑制炎症诱导的血管生成，并支持使用药理学 Caspase-8 抑制剂作为治疗 CNV 和其他血管生成性疾病的新方法。
