title: TNFa knockdown in the retina promotes cone survival in a mouse model of autosomal dominant retinitis pigmentosa.
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.
authors.affiliation: University of Alabama at Birmingham, Department of Optometry and Vision Science, United States.
authors.forename: Tapasi
authors.initials: T
authors.lastname: Rana
authors.affiliation: University of Alabama at Birmingham, Department of Optometry and Vision Science, United States.
authors.forename: Pravallika
authors.initials: P
authors.lastname: Kotla
authors.affiliation: University of Alabama at Birmingham, Department of Optometry and Vision Science, United States.
authors.forename: Roderick
authors.initials: R
authors.lastname: Fullard
authors.affiliation: University of Alabama at Birmingham, Department of Optometry and Vision Science, United States. Electronic address: mgortk@uab.edu.
authors.forename: Marina
authors.initials: M
authors.lastname: Gorbatyuk
mesh_terms: D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D005260:Female; D055785:Gene Knockdown Techniques; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017949:Retinal Cone Photoreceptor Cells / Q000166:cytology / Q000276:immunology / Q000473:pathology*; D017948:Retinal Rod Photoreceptor Cells; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000276:immunology; D056811:Unfolded Protein Response
chemical_list: D014409:Tumor Necrosis Factor-alpha
keywords: Cone survival; Retinal degeneration; T17M rhodopsin; Transgenic mice; Tumor necrosis factor; Unfolded protein response