Differential Role of TNF-Alpha Receptors in Choroidal Neovascularization

Abstract

Purpose: : Tumor necrosis factor alpha (TNF)-α contributes to inflammation-associated angiogenesis. This study investigates the role of TNF-α receptors p55 and p75 in the development of choroidal neovascularization (CNV).

Methods: : CNV was induced in TNFRp55 -/- and TNFRp75 -/- mice and their WT controls by laser damage to the Bruch's membrane. Pathological angiogenesis was estimated by fluorescein angiography and histology. Inflammatory cell invasion was investigated by clodronic acid depletion of circulating macrophages and immunochemistry and the apoptotic activity via TUNEL assay, and caspase-3, and caspase-8 expression. Letal irradiation and transplantation with adult bone-marrow derived cells was performed to investigate TNF-alpha-mediated recruitment of inflammatory cells to CNV lesions.

Results: : Severe CNV lesions and increased macrophage invasion were observed in TNFRp55-/- compared to WT and TNFRp75-/- mice. Increased immunoreactivity for Bmx/Etk kinase corresponded to the severity of CNV formation. Reduced pathological angiogenesis and macrophage invasion in TNFRp75-/- mice (vs. WT and TNFRp55-/-) was accompanied with enhanced endothelial cell apoptosis and caspase-3, and caspase-8 activation. Macrophage infiltration of the scars was reduced in TNFRp75 knock-out in comparison to WT recipients. Transplantation of bone marrow cells that lack receptor p75 to WT and TNFRp75-/- recipient reduced further the recruitment of inflammatory cells and CNV formation.

Conclusions: : Receptor p75 promotes recruitment of inflammatory cells to the site of injury and exacerbated pathological angiogenesis probably via Bmx/Etk-kinase dependent pathway in the absence of receptor p55. On the other hand, receptor p55-dependent apoptosis in the absence of receptor p75 lead to reduced inflammatory response and CNV lesions after laser treatment. This demonstrates the potential of specific targeting of TNF-α receptors for future therapies of inflammation-associated choroidal neovascularization.

Keywords: age-related macular degeneration • choroid: neovascularization • inflammation