title: NLRP3 inflammasome activation drives bystander cone photoreceptor cell death in a P23H rhodopsin model of retinal degeneration.
abstract: The molecular signaling leading to cell death in hereditary neurological diseases such as retinal degeneration is incompletely understood. Previous neuroprotective studies have focused on apoptotic pathways; however, incomplete suppression of cell death with apoptosis inhibitors suggests that other mechanisms are at play. Here, we report that different signaling pathways are activated in rod and cone photoreceptors in the P23H rhodopsin mutant rat, a model representing one of the commonest forms of retinal degeneration. Up-regulation of the RIP1/RIP3/DRP1 axis and markedly improved survival with necrostatin-1 treatment highlighted necroptosis as a major cell-death pathway in degenerating rod photoreceptors. Conversely, up-regulation of NLRP3 and caspase-1, expression of mature IL-1β and IL-18 and improved cell survival with N-acetylcysteine treatment suggested that inflammasome activation and pyroptosis was the major cause of cone cell death. This was confirmed by generation of the P23H mutation on an Nlrp3-deficient background, which preserved cone viability. Furthermore, Brilliant Blue G treatment inhibited inflammasome activation, indicating that the 'bystander cell death' phenomenon was mediated through the P2RX7 cell-surface receptor. Here, we identify a new pathway in cones for bystander cell death, a phenomenon important in development and disease in many biological systems. In other retinal degeneration models different cell-death pathways are activated, which suggests that the particular pathways that are triggered are to some extent genotype-specific. This also implies that neuroprotective strategies to limit retinal degeneration need to be customized; thus, different combinations of inhibitors will be needed to target the specific pathways in any given disease.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of British Columbia, 2550 Willow Street, Vancouver, BC, Canada V5Z 3N9.
authors.forename: Ishaq A
authors.initials: IA
authors.lastname: Viringipurampeer
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of British Columbia, 2550 Willow Street, Vancouver, BC, Canada V5Z 3N9.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Metcalfe
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of British Columbia, 2550 Willow Street, Vancouver, BC, Canada V5Z 3N9.
authors.forename: Abu E
authors.initials: AE
authors.lastname: Bashar
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of British Columbia, 2550 Willow Street, Vancouver, BC, Canada V5Z 3N9.
authors.forename: Olena
authors.initials: O
authors.lastname: Sivak
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of British Columbia, 2550 Willow Street, Vancouver, BC, Canada V5Z 3N9.
authors.forename: Anat
authors.initials: A
authors.lastname: Yanai
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of British Columbia, 2550 Willow Street, Vancouver, BC, Canada V5Z 3N9.
authors.forename: Zeinabsadat
authors.initials: Z
authors.lastname: Mohammadi
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of British Columbia, 2550 Willow Street, Vancouver, BC, Canada V5Z 3N9.
authors.forename: Orson L
authors.initials: OL
authors.lastname: Moritz
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of British Columbia, 2550 Willow Street, Vancouver, BC, Canada V5Z 3N9.
authors.forename: Cheryl Y
authors.initials: CY
authors.lastname: Gregory-Evans
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of British Columbia, 2550 Willow Street, Vancouver, BC, Canada V5Z 3N9 kge30@mail.ubc.ca.
authors.forename: Kevin
authors.initials: K
authors.lastname: Gregory-Evans
mesh_terms: D000818:Animals; D024201:Bystander Effect / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D058847:Inflammasomes / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D051381:Rats; D055647:Rats, Transgenic; D017949:Retinal Cone Photoreceptor Cells / Q000166:cytology* / Q000187:drug effects; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017948:Retinal Rod Photoreceptor Cells / Q000166:cytology* / Q000187:drug effects; D012243:Rhodopsin / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007093:Imidazoles; D007211:Indoles; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C573346:Nlrp3 protein, rat; C507699:necrostatin-1; D012243:Rhodopsin