Cellular and molecular mechanisms of AIM2 and NLRP3 inflammasome activation in age-related macular degeneration

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SUMMARY: 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 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 through the generation of IL-1b and which has been reported to be activated in AMD, has become an area of much interest in the AMD field. However, previous studies have focused mainly on the NLRP3 inflammasome in RPE cells and conflicting data have resulted in an unclear picture of the role of the inflammasome for AMD pathogenesis. By utilizing a genetic mouse model of NV-AMD, Vegfahyper mice, we provide now new data that resolve key open questions in the AMD field and help explain some of the conflicting data. Our findings demonstrate that inflammasome activation in activated macrophages and microglia but not in RPE cells promotes CNV. Thus, a lack of inflammasome activity in the RPE does not mean that the inflammasome does not play a role in AMD pathogenesis. Furthermore, we provide evidence that inflammasome activation can occur in CNV macrophages and microglia despite NLRP3 deficiency. Based on these findings we propose that activation of both NLRP3 inflammasomes as well as non-NLRP3 inflammasomes in macrophages/microglia promotes CNV. Our new data in Vegfahyper mice and in eyes from patients with NV-AMD suggest that the AIM2 inflammasome is a key contributor to overall inflammasome activation in these macrophages and/or microglia. Thus, we hypothesize that both the NLRP3 and the AIM2 inflammasomes promote NV-AMD through their activation in macrophages and microglia that infiltrate and induce early CNV. Notably, a role of the AIM2 inflammasome for AMD pathogenesis has previously not been considered. Thus, our preliminary data and published work provide a strong scientific premise for these hypotheses, and the proposed experiments have a high novelty, high rigor, and strong clinical relevance, as their outcome will serve as a framework for novel therapies that target inflammasome activation in patients with NV-AMD. Our proposal will utilize both genetic as well as pharmacologic approaches in two well-established mouse models of NV-AMD as well as experiments in human AMD eyes, to define the roles of AIM2 and NLRP3 inflammasomes for NV-AMD.