TNFa knockdown in the retina promotes cone survival in a mouse model of autosomal dominant retinitis pigmentosa

Biochim Biophys Acta Mol Basis Dis. 2017 Jan;1863(1):92-102. doi: 10.1016/j.bbadis.2016.10.008. Epub 2016 Nov 14.

Abstract

Expression of T17M rhodopsin (T17M) in rods activates the Unfolded Protein Response (UPR) and leads to the development of autosomal dominant retinitis pigmentosa (adRP). The rod death occurs in adRP retinas prior to cone photoreceptor death, so the mechanism by which cone photoreceptors die remains unclear. Therefore, the goal of the study was to verify whether UPR in rods induces TNFa-mediated signaling to the cones and to determine whether the TNFa deficit could prevent adRP cone cell death. Primary rod photoreceptors and cone-derived 661W cells transfected with siRNA against TNFa were treated with tunicamycin to mimic activation of UPR in T17M retinas expressing normal and reduced TNFa levels. The 661W cells were then exposed to recombinant TNFa to evaluate cell viability. In vivo, the role of TNFa was assessed in T17M TNFa+/- mice by electroretinography, optical coherence tomography, histology, immunohistochemistry, and a cytokine enzyme-linked immunosorbent assay. Rods overexpressed and secreted TNFa in response to UPR activation. The recombinant TNFa treatment lowered the number of viable cones, inducing cell death through elevation of pro-inflammatory cytokines and caspase-3/7 activity. The TNFa deficiency significantly protected adRP retinas. The photopic ERG amplitudes and the number of surviving cones dramatically increased in T17M TNFa+/- mice. This neuroprotection was associated with a reduced level of pro-inflammatory cytokines. Our results indicate that rod photoreceptors, following UPR activation during adRP progression, secrete TNFa and signal a self-destructive program to the cones, resulting in their cell death. TNFa therefore holds promise as a therapeutic target for treatment of adRP.

Keywords: Cone survival; Retinal degeneration; T17M rhodopsin; Transgenic mice; Tumor necrosis factor; Unfolded protein response.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Survival
  • Cells, Cultured
  • Female
  • Gene Knockdown Techniques*
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Retinal Cone Photoreceptor Cells / cytology
  • Retinal Cone Photoreceptor Cells / immunology
  • Retinal Cone Photoreceptor Cells / pathology*
  • Retinal Rod Photoreceptor Cells
  • Retinitis Pigmentosa / genetics*
  • Retinitis Pigmentosa / immunology
  • Retinitis Pigmentosa / pathology*
  • Tumor Necrosis Factor-alpha / genetics*
  • Tumor Necrosis Factor-alpha / immunology
  • Unfolded Protein Response

Substances

  • Tumor Necrosis Factor-alpha