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

年龄相关性黄斑变性中 AIM2 和 NLRP3 炎症小体激活的细胞和分子机制

• 批准号: 10584110
• 负责人: Alexander Georg Marneros
• 金额: $ 49.05万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584110
• 关键词: Affect; Age related macular degeneration; Area; CASP1 gene; Cells; Cellular Stress; Cholesterol; Choroid; Choroidal Neovascularization; Data; Disease; Disease Progression; Drug Targeting; Exudative age-related macular degeneration; Eye; Eye diseases; Generations; Genetic; Growth Factor; Human; Impairment; Infiltration; Inflammasome; Inflammatory; Lasers; Lesion; Long-Term Effects; Macrophage; Microglia; Molecular; Mus; Outcome; Oxidative Stress; Oxidative Stress Induction; Pathogenesis; Pathologic Neovascularization; Pathology; Pathway interactions; Patients; Pattern recognition receptor; Physiological; Play; Production; Publishing; Reactive Oxygen Species; Reporting; Research; Retina; Risk Factors; Role; Stimulus; Testing; Treatment Protocols; VEGFA gene; Work; aged; bevacizumab; cell injury; cell type; clinically relevant; ds-DNA; experimental study; inhibitor; interest; mouse model; new therapeutic target; novel strategies; novel therapeutics; pathogen; patient subsets; pharmacologic; pre-clinical; prevent; protein complex; side effect

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.

摘要：当前抗VEGF-A疗法抑制了一部分患者的脉络膜新生血管形成（CNV） 与新血管相关的黄斑变性（NV-AMD）。但是，这种抗的长期治疗 VEGF-A疗法可能会损害VEGF-A为 需要。此外，尽管连续抗VEGF-A治疗，疾病进展仍会发生。因此，新颖 迫切需要使用NV-AMD的疗法，以专门针对疾病相关的机制 损害了视网膜稳态功能所需的生长因子和细胞途径 脉络膜。抑制促进CNV的炎症途径将是一种有前途的新方法 不会干扰健康的视网膜和脉络膜细胞的正常功能。在这种情况下， 炎性体是一种促炎蛋白复合物，可通过 IL-1B的产生并据报道已在AMD中激活，已成为引起人们关注的领域 在AMD领域。然而，以前的研究主要集中在RPE细胞中的NLRP3炎症体和 相互矛盾的数据导致了炎症体对AMD发病机理的作用的不清楚。经过 利用NV-AMD的遗传鼠标模型，Vegfahyper小鼠，我们现在提供解决键打开的新数据 AMD领域中的问题并有助于解释一些相互矛盾的数据。我们的发现表明 活化巨噬细胞和小胶质细胞中的炎症体激活，但在RPE细胞中不促进CNV。因此， RPE中缺乏炎症活动并不意味着炎性体在AMD中不起作用 发病。此外，我们提供的证据表明CNV巨噬细胞中可能发生炎性体激活 和小胶质细胞，尽管缺乏NLRP3。基于这些发现，我们提出了两个NLRP3的激活 巨噬细胞/小胶质细胞中的炎性症以及非NLRP3炎症促进CNV。我们的新数据 在Vegfahyper小鼠和NV-AMD患者的眼睛中，AIM2炎症体是关键 这些巨噬细胞和/或小胶质细胞中总体炎症体激活的贡献者。因此，我们假设 NLRP3和AIM2发炎都通过巨噬细胞激活促进NV-AMD 和浸润并诱导早期CNV的小胶质细胞。值得注意的是，AMD的AIM2炎症体的角色 以前未考虑发病机理。因此，我们的初步数据和已发表的工作提供了 这些假设的有力科学前提，并且提出的实验具有很高的新颖性，高 严格和强大的临床相关性，因为它们的结果将成为针对目标的新型疗法的框架 NV-AMD患者的炎性体激活。我们的建议将同时利用遗传学和药理学 在两个NV-AMD的小鼠模型以及人类AMD眼中的实验中的接近 定义NV-AMD的AIM2和NLRP3炎症体的作用。