Innate Immunity and NLRP3 inflammasome activation in pathologic neovascularization

病理性新生血管形成中的先天免疫和 NLRP3 炎性体激活

• 批准号: 9319274
• 负责人: Alexander Georg Marneros
• 金额: $ 19.69万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9319274
• 关键词: Affect; Age related macular degeneration; Autophagocytosis; Biological Models; CASP1 gene; Cells; Data; Disease; Endothelial Cells; Experimental Models; Exudative age-related macular degeneration; Eye; Genetic; Growth; IL1R1 gene; In Vitro; Inflammasome; Inflammation; Inflammatory; Interleukin-1 beta; Lesion; Lipids; Mediating; Mus; Natural Immunity; Pathologic; Pathologic Neovascularization; Pathology; Pathway interactions; Patients; Play; Process; Reporting; Role; Signal Pathway; Signal Transduction; Structure of retinal pigment epithelium; System; TLR2 gene; Testing; Therapeutic; Vascular Endothelial Growth Factors; angiogenesis; base; cell type; experimental study; genetic approach; in vivo; in vivo Model; inhibitor/antagonist; mouse model; neovascular; neovascularization; novel; novel therapeutic intervention; oxidation; oxidative damage; therapeutic target

SUMMARY Pathologic neovascularization is an important aspect of the inflammatory process. NLRP3 inflammasome activation has been implicated as a major regulator of pathologic angiogenesis through secretion of proangiogenic factors (e.g. IL-1β). Targeting the NLRP3 inflammasome or its regulators may therefore represent a novel therapeutic approach to inhibit inflammation and pathologic neovascularization. For example, we could show in a novel genetic mouse model of VEGF-A-induced neovascular age-related macular degeneration (AMD) that genetic inactivation of the NLRP3 inflammasome can potently inhibit the manifestation of neovascular lesions. This mouse model of neovascular AMD serves as a particularly disease-relevant model system to assess the mechanisms through which the NLRP3 inflammasome promotes inflammation and pathologic angiogenesis. In vitro studies have suggested that autophagy and TLR-signaling pathways are important regulators of NLRP3 inflammasome activity. However, the role of these pathways for NLRP3 inflammasome activation and pathologic neovascularization in vivo remain unclear. We propose that increasing autophagy or inhibiting TLR-signaling could be utilized to control NLRP3 inflammasome activation. Here, we will use our novel genetic mouse model of neovascular AMD that allows precise quantitation of neovascular lesions as an experimental in vivo model system to determine the contributions of autophagy and TLR-signaling for NLRP3 inflammasome activation and subsequent pathologic angiogenesis using mouse genetic approaches. These experiments are likely to reveal the importance of these pathways as regulators of NLRP3 inflammasome-mediated inflammation. Moreover, our in vivo experiments have significant translational relevance and will help determine whether stimulating autophagic activity or inhibiting TLR-signaling represent promising novel therapeutic approaches to block pathologic angiogenesis in conditions such as neovascular AMD.

总结

项目成果

Distinct effects of complement and of NLRP3- and non-NLRP3 inflammasomes for choroidal neovascularization.

• DOI: 10.7554/elife.60194
• 发表时间: 2020-12-11
• 期刊: eLife
• 影响因子: 7.7
• 作者: Malsy J;Alvarado AC;Lamontagne JO;Strittmatter K;Marneros AG
• 通讯作者: Marneros AG

Role of inflammasome activation in neovascular age-related macular degeneration.

• DOI: 10.1111/febs.16278
• 发表时间: 2023-01
• 期刊: The FEBS journal