Abstract
Current anti-VEGF-A therapies inhibit choroidal neovascularization (CNV) in a subset of patients with neovascular age-related macular degeneration (NV-AMD). However, long-term treatment with such anti-VEGF-A therapies may impair physiological functions of the choriocapillaris and retina for which VEGF-A is needed. Moreover, disease progression can occur despite continuous anti-VEGF-A treatment. Thus, novel therapies for NV-AMD are urgently needed that target specifically disease-associated mechanisms without impairing growth factors and cellular pathways that are required for homeostatic functions of the retina and choroid. Inhibiting the inflammatory pathways that promote CNV would be such a promising novel approach that would likely not interfere with the normal functions of healthy retinal and choroidal cells. In this context, the inflammasome, a proinflammatory protein complex that promotes pathologic angiogenesis largely through generation of IL-1β and which has been reported to be activated in AMD, has become an area of much interest in the AMD field. However, most studies have focused mainly on the NLRP3 inflammasome in retinal pigment epithelial cells (RPE), and conflicting findings have resulted in an unclear picture of the role of the inflammasome for AMD pathogenesis. Recent data suggest that inflammasome activation in activated macrophages and retinal microglia but not in RPE cells promotes CNV. Furthermore, inflammasome activation can occur in CNV macrophages and microglia despite lack of NLRP3. Thus, activation of both NLRP3 inflammasomes as well as non-NLRP3 inflammasomes in macrophages/microglia at sites of CNV formation likely promote NV-AMD.