VEGF-A and the NLRP3 Inflammasome in Age-Related Macular Degeneration

Abstract

The pathomechanisms that lead to age-related macular degeneration (AMD) are only partially understood. The NLRP3 inflammasome has been shown to be activated in the retinal pigment epithelium (RPE) in eyes with AMD. However, it is not known whether inflammasome activation is a cause or consequence of pathologic changes in AMD. A roadblock to defining the role of inflammasome activation and pathways that regulate it for AMD has been the lack of a mouse model that forms AMD-like pathologies in an age-dependent manner in which the role of the inflammasome can be investigated using genetic studies. We have recently identified such a mouse model, in which increased VEGF-A levels result in early degenerative changes of the RPE, followed by cardinal features of both nonexudative and neovascular AMD. Importantly, higher VEGF-A levels lead to increased oxidative damage and a sub-retinal inflammatory infiltrate that are associated with NLRP3 inflammasome activation in the RPE. Targeting the NLRP3 inflammasome inhibited AMD-like pathologies in these mice. These findings suggest that inhibiting the NLRP3 inflammasome or pathways that regulate it may provide novel therapeutic approaches for the treatment of both forms of AMD.