Pharmacological Inhibition of Caspase-8 Suppresses Inflammation-Induced Angiogenesis in the Cornea.

Abstract

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.

• Authors: Yunzhe Tian, He Li, Xiuxing Liu, Lihui Xie, Zhaohao Huang, Weihua Li, Zhuang Li, Yuan Pan, Xiaoqing Chen, Wenru Su
• Journal: Biomolecules (Biomolecules) Vol. 10 Issue 2 (01 31 2020) ISSN: 2218-273X [Electronic] Switzerland
• PMID: 32023953 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Caspase Inhibitors
• Pecam1 protein, mouse
• Platelet Endothelial Cell Adhesion Molecule-1
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, mouse
• Casp8 protein, mouse
• Caspase 8
• Casp1 protein, mouse
• Caspase 1

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Caspase 1 (metabolism)
• Caspase 8 (genetics, metabolism)
• Caspase Inhibitors (pharmacology)
• Cornea (blood supply, pathology)
• Inflammation (drug therapy)
• Macrophages (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Neovascularization, Pathologic (drug therapy)
• Platelet Endothelial Cell Adhesion Molecule-1 (metabolism)
• RAW 264.7 Cells
• Toll-Like Receptor 4 (genetics, metabolism)
• Vascular Endothelial Growth Factor A (metabolism)