September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Non-canonical NLRP3 Inflammasome activation in Geographic Atrophy
Author Affiliations & Notes
  • Nagaraj Kerur
    Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, United States
  • Younghee Kim
    Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, United States
  • Shinichi Fukuda
    Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, United States
  • Reo Yasuma
    Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, United States
  • Ana Bastos-Carvalho
    Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, United States
  • Daipayan Banerjee
    Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, United States
  • Benjamin Fowler
    Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, United States
  • Tetsuhiro Yasuma
    Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, United States
  • Bradley D Gelfand
    Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, United States
  • Jayakrishna Ambati
    Ophthalmology and Visual Sciences, University of Kentucky, Lexington, Kentucky, United States
  • Footnotes
    Commercial Relationships   Nagaraj Kerur, None; Younghee Kim, None; Shinichi Fukuda, None; Reo Yasuma, None; Ana Bastos-Carvalho, None; Daipayan Banerjee, None; Benjamin Fowler, None; Tetsuhiro Yasuma, None; Bradley Gelfand, None; Jayakrishna Ambati, Allergan (R), Inflammasome Therapeutics (I), Inflammasome Therapeutics (S), iVeena Delivery Systems (I), iVeena Delivery Systems (P), iVeena Delivery Systems (S), iVeena Holdings (I), iVeena Holdings (P), iVeena Holdings (S), iVeena Pharmaceuticals (I), iVeena Pharmaceuticals (P), iVeena Pharmaceuticals (S), Olix Pharmaceuticals (S), University of Kentucky (P)
  • Footnotes
    Support  NIH grant EY024336
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 486. doi:
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      Nagaraj Kerur, Younghee Kim, Shinichi Fukuda, Reo Yasuma, Ana Bastos-Carvalho, Daipayan Banerjee, Benjamin Fowler, Tetsuhiro Yasuma, Bradley D Gelfand, Jayakrishna Ambati; Non-canonical NLRP3 Inflammasome activation in Geographic Atrophy. Invest. Ophthalmol. Vis. Sci. 2016;57(12):486.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Alu RNA-activated NLRP3 inflammasome activation is implicated in the RPE cell death in geographic atrophy (GA), an advanced form of age-related macular degeneration. A comprehensive understanding of the molecular determinants of inflammasome activation is critical for developing NLRP3 inflammasome-targeted rational therapeutic strategies for GA. Emerging evidence suggests involvement of a non-canonical inflammasome in which an upstream Caspase-4 (also known as Caspase-11 in mice) drives NLRP3 inflammasome activation. Here we seek to gain functional insights into whether and how Caspase-4 regulates the NLRP3 inflammasome in GA pathogenesis.

Methods : Human and mouse RPE cells were transfected with a plasmid encoding an Alu element (pAlu) or an in vitro transcribed Alu RNA. Inflammasome activation was assessed by monitoring Caspase-1 cleavage into its active form. RPE degeneration was induced in mice by subretinal transfection of pAlu, Alu RNA or Dicer1 siRNA. RPE degeneration was assessed by fundus photography and zonula occludens 1 (ZO-1) staining of RPE flat mounts. Caspase-4 activation was monitored by Western blotting.

Results : Increased abundance of activated Caspase-4 was observed in RPE lysates from atrophic AMD eyes. Alu RNA, pAlu and Dicer1 knockdown activated Caspase-4 in human and mouse RPE cells. Furthermore Alu exposure failed to induce inflammasome activation in cells and mice lacking Caspase-4. Consistent with these findings, Caspase-4-/- mice were resistant to RPE degeneration induced by Alu RNA, pAlu or Dicer1 siRNA.

Conclusions : Dicer1 deficit/Alu RNA-driven RPE degeneration in AMD is mediated by Caspase-4 dependent non-canonical NLRP3 inflammasome. Additional studies aimed at deciphering the mechanism of Caspase-4-driven non-canonical NLRP3 inflammasome activation by Alu RNA are ongoing.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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