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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.
Highlights
Angiogenesis is a fundamental process in growth
This study shows that pharmacological caspase-8 inhibition is a feasible and effective treatment strategy for corneal neovascularization (CNV) and identifies the key role of caspase-8 in CNV after corneal alkali burn (AB)
We found that corneal AB induced CNV and increased caspase-8 activity and that caspase-8 inhibition had substantial suppressive effects on CNV, with consistent decreases in caspase-8 activity, inflammatory cell infiltration, F4/80+ macrophage recruitment and activation, vascular endothelial growth factor-A (VEGF-A), inflammatory cytokines and chemokines expression in the cornea after corneal AB
Summary
Angiogenesis is a fundamental process in growth. It is vital for the pathogenesis of inflammation, cancer, atherosclerosis, rheumatoid arthritis, and ocular vascular diseases, such as diabetic retinopathy, age-related macular degeneration, and corneal neovascularization (CNV) [1,2,3,4,5,6,7]. Caspase-8, a member of caspase family with a well-characterized role in initiating cell apoptosis, has attracted increasing attention due to its immune properties [14,15,16]. It is a zymogen composed of an N-terminal prodomain and a C-terminal catalytic domain. Caspase-8 has recently been reported to mediate the activation of the Nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, comprising the NLRP3 scaffold, apoptosis-associated speck-like protein containing CARD (ASC) and caspase-1, which participates in various diseases, including autoimmune disorders, type 2 diabetes, atherosclerosis, gout, and obesity [15,22,23,24]. The involvement of caspase-8 in inflammation-associated angiogenesis and the underlying mechanisms are not yet clear
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