Evidence for the activation of pyroptotic and apoptotic pathways in RPE cells associated with NLRP3 inflammasome in the rodent eye
Open accessAbstract
BACKGROUND: Age-related macular degeneration (AMD) is a devastating eye disease causing irreversible vision loss in the elderly. Retinal pigment epithelium (RPE), the primary cell type that is afflicted in AMD, undergoes programmed cell death in the late stages of the disease. However, the exact mechanisms for RPE degeneration in AMD are still unresolved. The prevailing theories consider that each cell death pathway works independently and without regulation of each other. Building upon our previous work in which we induced a short burst of inflammasome activity in vivo, we now investigate the effects of prolonged inflammasome activity on RPE cell death mechanisms in rats. METHODS: Long-Evans rats received three intravitreal injections of amyloid beta (Aβ), once every 4 days, and were sacrificed at day 14. The vitreous samples were collected to assess the levels of secreted cytokines. The inflammasome activity was evaluated by both immunohistochemistry and western blot. The types of RPE cell death mechanisms were determined using specific cell death markers and morphological characterizations. RESULTS: We found robust inflammasome activation evident by enhanced caspase-1 immunoreactivity, augmented NF-κB nuclear translocalization, increased IL-1β vitreal secretion, and IL-18 protein levels. Moreover, we observed elevated proteolytic cleavage of caspase-3 and gasdermin D, markers for apoptosis and pyroptosis, respectively, in RPE-choroid tissues. There was also a significant reduction in the anti-apoptotic factor, X-linked inhibitor of apoptosis protein, consistent with the overall changes of RPE cells. Morphological analysis showed phenotypic characteristics of pyroptosis including RPE cell swelling. CONCLUSIONS: Our data suggest that two cell death pathways, pyroptosis and apoptosis, were activated in RPE cells after exposure to prolonged inflammasome activation, induced by a drusen component, Aβ. The involvement of two distinct cell death pathways in RPE sheds light on the potential interplay between these pathways and provides insights on the future development of therapeutic strategies for AMD.
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Microglia can phagocytose and degrade pathologic tau, neuronal synapses, or whole live neurons, although not very efficiently.
“Microglia can phagocytose and degrade pathologic tau, neuronal synapses, or whole live neurons, although not very efficiently [188, 189].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [188]
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- Authors
- Gao, J., Cui, J. Z., To, E., Cao, S., & Matsubara, J. A.
- Affiliations
- University of British Columbia (CA)
- Corresponding author
- Matsubara, Joanne A.
- Venue
- Journal of Neuroinflammation
- Published
- 2018-01-12
- Volume
- 15
- Issue
- 1
- Pages
- 15-15
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC5766992
- OpenAlex
- W2782813514
- Cited by
- 83
- References
- 46
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 10 · 2023: 5 · 2022: 11 · 2021: 16 · 2020: 21 · 2019: 8
- FWCI
- 11.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- cIRcle (University of British Columbia) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Canadian Institutes of Health Research (MOP126195)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
- Keywords
- age-related macular degeneration, retinal pigment epithelium, NLRP3 inflammasome, pyroptosis, apoptosis, amyloid-beta, drusen, caspase-1, gasdermin D, caspase-3, IL-1β, IL-18, NF-κB, XIAP, programmed cell death, intravitreal injection
- MeSH terms
- Pyroptosis, NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Female, Rodentia, Vitreous Body, Signal Transduction, Apoptosis, Rats, Long-Evans, Rats, Retinal Pigment Epithelium
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