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

Elife. 2020 Dec 11;9:e60194. doi: 10.7554/eLife.60194.

Abstract

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.

Keywords: NLRP3; VEGF-A; caspase-1; choroidal neovascularization; complement; immunology; inflammasome; inflammation; mouse; neovascular age-related macular degeneration.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caspase 1 / genetics
  • Caspase 1 / metabolism
  • Caspases, Initiator / genetics
  • Caspases, Initiator / metabolism
  • Choroidal Neovascularization / genetics
  • Choroidal Neovascularization / immunology
  • Choroidal Neovascularization / metabolism*
  • Choroidal Neovascularization / pathology
  • Complement Activation*
  • Complement System Proteins / metabolism*
  • Disease Models, Animal
  • Inflammasomes / genetics
  • Inflammasomes / metabolism*
  • Macular Degeneration / genetics
  • Macular Degeneration / immunology
  • Macular Degeneration / metabolism*
  • Macular Degeneration / pathology
  • Mice, Knockout
  • Mice, Transgenic
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • 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

Substances

  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Complement System Proteins
  • Casp4 protein, mouse
  • Caspases, Initiator
  • Casp1 protein, mouse
  • Caspase 1

Grant support

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.