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-1?). 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.

Public Health Relevance

The NLRP3 inflammasome is an important component of inflammation in several pathologic conditions and promotes abnormal angiogenesis through activation of proangiogenic IL-1?. Targeting the NLRP3 inflammasome can inhibit pathologic neovascularization. Thus, critical regulators of the NLRP3 inflammasome could present promising therapeutic targets to inhibit inflammation mediated by inflammasome activation. Here, we will assess the in vivo consequences of targeting autophagy or TLR-signaling for NLRP3 inflammasome activation and pathologic neovascularization.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21EY027104-02
Application #
9319274
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mckie, George Ann
Project Start
2016-08-01
Project End
2018-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114