TLR4/TRIF/Caspase-8/Caspase-1 Pathway in Choroidal Endothelial Cells Promotes Choroidal Neovascularization

Purpose: The purpose of this study was to investigate the role and mechanism of Caspase-8 in the development of choroidal neovascularization induced by age-related macular degeneration, with the aim of identifying a potential therapeutic target for neovascular age-related macular degeneration.

Methods: Mouse models of laser photocoagulation-induced choroidal neovascularization and hypoxic human choroidal endothelial cells were utilized to examine the involvement of Caspase-8 in choroidal neovascularization development. The Toll-like Receptor 4/TIR domain-containing adaptor molecule 1/Caspase-8 pathway was explored in hypoxic human choroidal endothelial cells to elucidate its contribution to pathological angiogenesis. Various experimental techniques, including inhibition assays and immunoblotting analysis, were employed to assess the effects and mechanisms of Caspase-8 activation.

Results: Inhibition of Caspase-8 demonstrated attenuated choroidal neovascularization development in mice subjected to laser photocoagulation. Activation of the Toll-like Receptor 4/TIR domain-containing adaptor molecule 1/Caspase-8 pathway was observed in hypoxic human choroidal endothelial cells. Upon activation by the Toll-like Receptor 4/TIR domain-containing adaptor molecule 1 axis, Caspase-8 directly cleaved Caspase-1, leading to the cleavage of interleukin-1β and interleukin-18 by Caspase-1. Consequently, activation of interleukin-1β and interleukin-18 through the Toll-like Receptor 4/TIR domain-containing adaptor molecule 1/Caspase-8/Caspase-1 pathway promoted the proliferative, migratory, and tube-forming abilities of hypoxic human choroidal endothelial cells.

Conclusion: The findings of this study indicate that Caspase-8 plays a crucial role in promoting choroidal neovascularization by activating interleukin-1β and interleukin-18 through the Toll-like Receptor 4/TIR domain-containing adaptor molecule 1/Caspase-8/Caspase-1 pathway in choroidal endothelial cells. Therefore, targeting Caspase-8 may hold promise as a therapeutic approach for neovascular age-related macular degeneration.

Caspase-8; caspase-1; choroidal endothelial cells; choroidal neovascularization.