ArticleHuman molecular genetics2016
NLRP3 inflammasome activation drives bystander cone photoreceptor cell death in a P23H rhodopsin model of retinal degeneration.
Article in Human molecular genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Who cites it
58 citing papers in PubMed, 86 citations in OpenAlex.
- Safety, pharmacokinetics and target engagement of novel RIPK1 inhibitor SAR443060 (DNL747) for neurodegenerative disorders: Randomized, placebo-controlled, double-blind phase I/Ib studies in healthy subjects and patients.Clinical and translational science · 2022Trial
- The Oxidative-Mitochondrial-Inflammatory Axis in Retinitis Pigmentosa: Extracellular mtDNA as Biomarker and Therapeutic Read-Out.Antioxidants (Basel, Switzerland) · 2026Review
- Oxidative DNA damage drives apoptotic photoreceptor loss in NMNAT1-associated inherited retinal degeneration: a therapeutic opportunity.Cell death & disease · 2026Article
- Inhibition of galanin receptor 3 slows down retina degeneration in retinitis pigmentosa through modulation of inflammatory and oxidative stress response.Scientific reports · 2026Article
- Emerging Roles of Regulated Cell Death-mediated Inflammation in Pathophysiology of Ocular Diseases.Journal of ophthalmic & vision research · 2026Review
- Neuroprotection of photoreceptors by combined inhibition of both Fas and autophagy pathways in P23H mice.Cell death & disease · 2025Article
- Mechanisms of Rhodopsin-Related Inherited Retinal Degeneration and Pharmacological Treatment Strategies.Cells · 2025Review
- When do patients with retinitis pigmentosa present to ophthalmologists? A multi-centre retrospective study.Eye (London, England) · 2024Article
- Preservation of retinal structure and function in two mouse models of inherited retinal degeneration by ONL1204, an inhibitor of the Fas receptor.Cell death & disease · 2024Article
- The contribution of pattern recognition receptor signalling in the development of age related macular degeneration: the role of toll-like-receptors and the NLRP3-inflammasome.Journal of neuroinflammation · 2024Review
- Immunology of Retinitis Pigmentosa and Gene Therapy-Associated Uveitis.Cold Spring Harbor perspectives in medicine · 2024Review
- Molecular basis of retinal remodeling in a zebrafish model of retinitis pigmentosa.Cellular and molecular life sciences : CMLS · 2023Article
- Endoplasmic reticulum stress: molecular mechanism and therapeutic targets.Signal transduction and targeted therapy · 2023Review
- Article
- Inhibition of Galectins and the P2X7 Purinergic Receptor as a Therapeutic Approach in the Neurovascular Inflammation of Diabetic Retinopathy.International journal of molecular sciences · 2023Review
- Novel compound heterozygous variants in theFrontiers in cell and developmental biology · 2023Article
- Targeting Necroptosis: A Novel Therapeutic Option for Retinal Degenerative Diseases.International journal of biological sciences · 2023Review
- miR-181a/b downregulation: a mutation-independent therapeutic approach for inherited retinal diseases.EMBO molecular medicine · 2022Article
- Loss of Fas Receptor Function Preserves Photoreceptor Structure and Function in Two Mouse Models of Inherited Retinal Degeneration.Investigative ophthalmology & visual science · 2022Article
- Long Non-coding RNAs: Pivotal Epigenetic Regulators in Diabetic Retinopathy.Current genomics · 2022Review
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.