title: NLRP3 inflammasome blockade inhibits VEGF-A-induced age-related macular degeneration.
abstract: The NLRP3 inflammasome is activated in age-related macular degeneration (AMD), but it remains unknown whether its activation contributes to AMD pathologies. VEGF-A is increased in neovascular ("wet") AMD, but it is not known whether it plays a role in inflammasome activation, whether an increase of VEGF-A by itself is sufficient to cause neovascular AMD and whether it can contribute to nonexudative ("dry") AMD that often co-occurs with the neovascular form. Here, it is shown that an increase in VEGF-A results in NLRP3 inflammasome activation and is sufficient to cause both forms of AMD pathologies. Targeting NLRP3 or the inflammasome effector cytokine IL-1β inhibits but does not prevent VEGF-A-induced AMD pathologies, whereas targeting IL-18 promotes AMD. Thus, increased VEGF-A provides a unifying pathomechanism for both forms of AMD; combining therapeutic inhibition of both VEGF-A and IL-1β or the NLRP3 inflammasome is therefore likely to suppress both forms of AMD.
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA; Department of Dermatology, Harvard Medical School, Charlestown, MA 02129, USA. Electronic address: amarneros@partners.org.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Marneros
mesh_terms: D000367:Age Factors; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000276:immunology* / Q000378:metabolism; D008268:Macular Degeneration / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D042461:Vascular Endothelial Growth Factor A