NLRP3 inflammasome blockade inhibits VEGF-A-induced age-related macular degeneration

Cell Rep. 2013 Sep 12;4(5):945-58. doi: 10.1016/j.celrep.2013.08.002. Epub 2013 Sep 5.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Age Factors
  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology*
  • Carrier Proteins / metabolism
  • Humans
  • Inflammasomes / immunology*
  • Inflammasomes / metabolism
  • Macular Degeneration / immunology*
  • Macular Degeneration / metabolism
  • Macular Degeneration / pathology
  • Mice
  • Mice, Transgenic
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Signal Transduction
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor A / immunology

Substances

  • Carrier Proteins
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Nlrp3 protein, mouse
  • Vascular Endothelial Growth Factor A