The TSPO-NOX1 axis controls phagocyte-triggered pathological angiogenesis in the eye

Nat Commun. 2020 Jun 1;11(1):2709. doi: 10.1038/s41467-020-16400-8.

Abstract

Aberrant immune responses including reactive phagocytes are implicated in the etiology of age-related macular degeneration (AMD), a major cause of blindness in the elderly. The translocator protein (18 kDa) (TSPO) is described as a biomarker for reactive gliosis, but its biological functions in retinal diseases remain elusive. Here, we report that tamoxifen-induced conditional deletion of TSPO in resident microglia using Cx3cr1CreERT2:TSPOfl/fl mice or targeting the protein with the synthetic ligand XBD173 prevents reactivity of phagocytes in the laser-induced mouse model of neovascular AMD. Concomitantly, the subsequent neoangiogenesis and vascular leakage are prevented by TSPO knockout or XBD173 treatment. Using different NADPH oxidase-deficient mice, we show that TSPO is a key regulator of NOX1-dependent neurotoxic ROS production in the retina. These data define a distinct role for TSPO in retinal phagocyte reactivity and highlight the protein as a drug target for immunomodulatory and antioxidant therapies for AMD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Gene Expression Regulation / drug effects
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Microglia / drug effects
  • Microglia / metabolism
  • NADPH Oxidase 1 / genetics*
  • NADPH Oxidase 1 / metabolism
  • Neovascularization, Pathologic / genetics*
  • Neovascularization, Pathologic / metabolism
  • Phagocytes / drug effects
  • Phagocytes / metabolism*
  • Purines / pharmacology
  • Reactive Oxygen Species / metabolism
  • Receptors, GABA / genetics*
  • Receptors, GABA / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Wet Macular Degeneration / genetics*
  • Wet Macular Degeneration / metabolism

Substances

  • Bzrp protein, mouse
  • N-benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide
  • Purines
  • Reactive Oxygen Species
  • Receptors, GABA
  • NADPH Oxidase 1
  • NOX1 protein, mouse