Neutrophils homing into the retina trigger pathology in early age-related macular degeneration

Commun Biol. 2019 Sep 20;2:348. doi: 10.1038/s42003-019-0588-y. eCollection 2019.

Abstract

Age-related macular degeneration (AMD) is an expanding problem as longevity increases worldwide. While inflammation clearly contributes to vision loss in AMD, the mechanism remains controversial. Here we show that neutrophils are important in this inflammatory process. In the retinas of both early AMD patients and in a mouse model with an early AMD-like phenotype, we show neutrophil infiltration. Such infiltration was confirmed experimentally using ribbon-scanning confocal microscopy (RSCM) and IFNλ- activated dye labeled normal neutrophils. With neutrophils lacking lipocalin-2 (LCN-2), infiltration was greatly reduced. Further, increased levels of IFNλ in early AMD trigger neutrophil activation and LCN-2 upregulation. LCN-2 promotes inflammation by modulating integrin β1 levels to stimulate adhesion and transmigration of activated neutrophils into the retina. We show that in the mouse model, inhibiting AKT2 neutralizes IFNλ inflammatory signals, reduces LCN-2-mediated neutrophil infiltration, and reverses early AMD-like phenotype changes. Thus, AKT2 inhibitors may have therapeutic potential in early, dry AMD.

Keywords: Ageing; Interferons; Mechanisms of disease.

Publication types

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

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Biomarkers
  • Disease Models, Animal
  • Female
  • Gene Expression
  • Humans
  • Immunophenotyping
  • Interferon-gamma / metabolism
  • Lipocalin-2 / genetics
  • Lipocalin-2 / metabolism
  • Macular Degeneration / etiology*
  • Macular Degeneration / metabolism*
  • Macular Degeneration / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Neutrophil Infiltration
  • Neutrophils / immunology*
  • Neutrophils / metabolism*
  • Neutrophils / pathology
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Reactive Oxygen Species / metabolism
  • Retina / immunology*
  • Retina / metabolism*
  • Retina / pathology

Substances

  • Biomarkers
  • LCN2 protein, human
  • Lipocalin-2
  • Reactive Oxygen Species
  • Interferon-gamma
  • AKT2 protein, human
  • Proto-Oncogene Proteins c-akt