Abstract
Purpose: :
Amyloid β (Aβ) is accumulated within drusen and reportedly critical for pathogenesis of age-related macular degeneration (AMD). Endothelial progenitor cells (EPC) contributed to the development of CNV via matrix degrading enzyme; cathepsin L. We previously reported that Aβ enhanced the production of pro-inflammatory cytokines in EPC (ARVO2010). In the present study we investigated the molecular mechanism of the recruitment of EPC to subretinal space secondary to Aβ accumulation.
Methods: :
EPC were isolated from the cultivation of mononuclear cells in human cord blood from healthy newborns. EPC were stimulated by Aβ or pro-inflammatory cytokines (IL-1β, TNF-α) . The mRNA expression and protein production of fractalkine and its receptor; CX3CR1 was analyzed by real-time PCR and western blot. Migratory activity was measured by Boyden chamber assay. The role of CX3CR1 in choroidal neovascularization (CNV) development was analyzed using laser-induced CNV model.
Results: :
IL-1β, TNF-α significantly increased the expression and protein production of fractalkine. Aβ treatment induced a significant increase of CX3CR1 expression and protein production. In Boyden chamber assay, fractalkine caused a remarkable migration of EPC in a dose-dependent manner. Fractalkine-induced migration of EPC was significantly enhanced in Aβ-treated EPC compared to non-treated EPC. Laser-induced CNV was significantly suppressed in CX3CR1-/- mice compared to wild type mice.
Conclusions: :
These results suggest the possibility that Aβ causes the migration of EPC to the area of drusen via up-regulation of CX3CR1 as well as cytokine-induced up-regulation of fractalkine. This phenomenon might be an important process for the CNV development in AMD.
Keywords: age-related macular degeneration • choroid: neovascularization • pathology: experimental