cGAS drives noncanonical-inflammasome activation in age-related macular degeneration

Nat Med. 2018 Jan;24(1):50-61. doi: 10.1038/nm.4450. Epub 2017 Nov 27.

Abstract

Geographic atrophy is a blinding form of age-related macular degeneration characterized by retinal pigmented epithelium (RPE) death; the RPE also exhibits DICER1 deficiency, resultant accumulation of endogenous Alu-retroelement RNA, and NLRP3-inflammasome activation. How the inflammasome is activated in this untreatable disease is largely unknown. Here we demonstrate that RPE degeneration in human-cell-culture and mouse models is driven by a noncanonical-inflammasome pathway that activates caspase-4 (caspase-11 in mice) and caspase-1, and requires cyclic GMP-AMP synthase (cGAS)-dependent interferon-β production and gasdermin D-dependent interleukin-18 secretion. Decreased DICER1 levels or Alu-RNA accumulation triggers cytosolic escape of mitochondrial DNA, which engages cGAS. Moreover, caspase-4, gasdermin D, interferon-β, and cGAS levels were elevated in the RPE in human eyes with geographic atrophy. Collectively, these data highlight an unexpected role of cGAS in responding to mobile-element transcripts, reveal cGAS-driven interferon signaling as a conduit for mitochondrial-damage-induced inflammasome activation, expand the immune-sensing repertoire of cGAS and caspase-4 to noninfectious human disease, and identify new potential targets for treatment of a major cause of blindness.

Publication types

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

MeSH terms

  • Animals
  • DEAD-box RNA Helicases / genetics
  • Geographic Atrophy / enzymology*
  • Humans
  • Inflammasomes / metabolism*
  • Interferon Type I / metabolism
  • Mice
  • Nucleotidyltransferases / metabolism*
  • Retinal Pigment Epithelium / metabolism
  • Ribonuclease III / genetics
  • Signal Transduction

Substances

  • Inflammasomes
  • Interferon Type I
  • MB21D1 protein, human
  • Nucleotidyltransferases
  • DICER1 protein, human
  • Ribonuclease III
  • DEAD-box RNA Helicases