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

• Published in: eLife Vol. 9
• Main Authors: Malsy, Jakob, Alvarado, Andrea C, Lamontagne, Joseph O, Strittmatter, Karin, Marneros, Alexander G
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 11.12.2020; eLife Sciences Publications, Ltd; eLife Sciences Publications Ltd
• Subjects: Analysis; Animals; Caspase 1 - genetics; Caspase 1 - metabolism; caspase-1; Caspases, Initiator - genetics; Caspases, Initiator - metabolism; choroidal neovascularization; Choroidal Neovascularization - genetics; Choroidal Neovascularization - immunology; Choroidal Neovascularization - metabolism; Choroidal Neovascularization - pathology; complement; Complement Activation; Complement System Proteins - metabolism; Disease Models, Animal; Immunology and Inflammation; inflammasome; Inflammasomes - genetics; Inflammasomes - metabolism; Inflammation; Macular degeneration; Macular Degeneration - genetics; Macular Degeneration - immunology; Macular Degeneration - metabolism; Macular Degeneration - pathology; Mice, Knockout; Mice, Transgenic; neovascular age-related macular degeneration; Neovascularization; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3; Retinal Pigment Epithelium - immunology; Retinal Pigment Epithelium - metabolism; Retinal Pigment Epithelium - pathology; Signal Transduction; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; neovascular age-related macular degeneration; mouse; choroidal neovascularization; inflammation; inflammasome; NLRP3; VEGF-A; complement; caspase-1; immunology
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.60194

NLRP3 inflammasome activation and complement-mediated inflammation have been implicated in promoting choroidal neovascularization (CNV) in age-related macular degeneration (AMD), but central questions regarding their contributions to AMD pathogenesis remain unanswered. Key open questions are (1) whether NLRP3 inflammasome activation mainly in retinal pigment epithelium (RPE) or rather in non-RPE cells promotes CNV, (2) whether inflammasome activation in CNV occurs via NLRP3 or also through NLRP3-independent mechanisms, and (3) whether complement activation induces inflammasome activation in CNV. Here we show in a neovascular AMD mouse model that NLRP3 inflammasome activation in non-RPE cells but not in RPE cells promotes CNV. We demonstrate that both NLRP3-dependent and NLRP3-independent inflammasome activation mechanisms induce CNV. Finally, we find that complement and inflammasomes promote CNV through independent mechanisms. Our findings uncover an unexpected role of non-NLRP3 inflammasomes for CNV and suggest that combination therapies targeting inflammasomes and complement may offer synergistic benefits to inhibit CNV.