Deletion of thioredoxin-interacting protein preserves retinal neuronal function by preventing inflammation and vascular injury

Br J Pharmacol. 2014 Mar;171(5):1299-313. doi: 10.1111/bph.12535.


Background and purpose: Retinal neurodegeneration is an early and critical event in several diseases associated with blindness. Clinically, therapies that target neurodegeneration fail. We aimed to elucidate the multiple roles by which thioredoxin-interacting protein (TXNIP) contributes to initial and sustained retinal neurodegeneration.

Experimental approach: Neurotoxicity was induced by intravitreal injection of NMDA into wild-type (WT) and TXNIP-knockout (TKO) mice. The expression of apoptotic and inflammatory markers was assessed by immunohistochemistry, elisa and Western blot. Microvascular degeneration was assessed by periodic acid-Schiff and haematoxylin staining and retinal function by electroretinogram.

Key results: NMDA induced early (1 day) and significant retinal PARP activation, a threefold increase in TUNEL-positive nuclei and 40% neuronal loss in ganglion cell layer (GCL); and vascular permeability in WT but not TKO mice. NMDA induced glial activation, expression of TNF-α and IL-1β that co-localized with Müller cells in WT but not TKO mice. In parallel, NMDA triggered the expression of NOD-like receptor protein (NLRP3), activation of caspase-1, and release of IL-1β and TNF-α in primary WT but not TKO Müller cultures. After 14 days, NMDA induced 1.9-fold microvascular degeneration, 60% neuronal loss in GCL and increased TUNEL-labelled cells in the GCL and inner nuclear layer in WT but not TKO mice. Electroretinogram analysis showed more significant reductions in b-wave amplitudes in WT than in TKO mice.

Conclusion and implications: Targeting TXNIP expression prevented early retinal ganglion cell death, glial activation, retinal inflammation and secondary neuro/microvascular degeneration and preserved retinal function. TXNIP is a promising new therapeutic target for retinal neurodegenerative diseases.

Keywords: ERG; IL-1β; Müller cell; NMDA; TNF-α; TXNIP; acellular capillary; apoptosis; neurotoxicity; retina; vascular permeability.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Animals
  • Apoptosis / drug effects
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cells, Cultured
  • Ependymoglial Cells / drug effects
  • Ependymoglial Cells / metabolism
  • Female
  • Glaucoma, Open-Angle / metabolism
  • Humans
  • Inflammation / prevention & control
  • Interleukin-1beta / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • N-Methylaspartate
  • Neurotoxicity Syndromes / metabolism*
  • Neurotoxicity Syndromes / prevention & control
  • Retina / drug effects
  • Retina / metabolism*
  • Thioredoxin-Disulfide Reductase / metabolism
  • Thioredoxins / genetics
  • Thioredoxins / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism
  • Vascular System Injuries / prevention & control


  • Carrier Proteins
  • Interleukin-1beta
  • Tumor Necrosis Factor-alpha
  • Txnip protein, mouse
  • 3-nitrotyrosine
  • Tyrosine
  • Thioredoxins
  • N-Methylaspartate
  • Thioredoxin-Disulfide Reductase