Evidence map›Paper›PMID 23221073›Full record

ArticleInvestigative ophthalmology & visual science2013

NLRP3 inflammasome activation in retinal pigment epithelial cells by lysosomal destabilization: implications for age-related macular degeneration.

Wen Allen Tseng, Thuzar Thein, Kati Kinnunen, Kameran Lashkari, Meredith S Gregory, Patricia A D'Amore, Bruce R Ksander

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Investigative ophthalmology & visual science, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 189 papers.

0numbers the graph read from it
0cells of the map it votes in
189citing papers in PubMed
8.3field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

189 citing papers in PubMed, 282 citations in OpenAlex.

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129 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

7 authors at 4 institutions in 2 countries.

Wen Allen TsengSchepens Eye Research Institute/Massachusetts Eye and Ear, Boston, Massachusetts, USA.
Thuzar Thein
Kati Kinnunen
Kameran Lashkari
Meredith S Gregory
Patricia A D'Amore
Bruce R Ksander
Massachusetts Eye and Ear Infirmary · USSmith-Kettlewell Eye Research Institute · USHarvard University · USUniversity of Eastern Finland · FI

Funding

Molecular, Cellular, & Developmental Dynamics PhD ProgramT32GM007226 · NIGMS · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI VAN VACTOR, DAVID L. · 1985 to 2021
$14.4M
The Role of the NALP3 Inflammasome in Age-Related Macular DegenerationF31AG039245 · NIA · HARVARD MEDICAL SCHOOL · PI TSENG, WEN ALLEN · 2011 to 2013
$81k
NEI NIH HHS EY05435NIA NIH HHS AG039245NIA NIH HHS F31 AG039245NIGMS NIH HHS GM07226NIGMS NIH HHS T32 GM007226
6 · The paper itself

Abstract

purposeTo evaluate the effect of lysosomal destabilization on NLRP3 inflammasome activation in RPE cells and to investigate the mechanisms by which inflammasome activation may contribute to the pathogenesis of age-related macular degeneration (AMD).

methodsHuman ocular tissue sections from patients with geographic atrophy or neovascular AMD were stained for NLRP3 and compared to tissues from age-matched controls. Expression of the IL-1β precursor, pro-IL-1β, was induced in ARPE-19 cells by IL-1α treatment. Immunoblotting was performed to assess expression of NLRP3 inflammasome components (NLRP3, ASC, and procaspase-1) and pro-IL-1β in ARPE-19 cells. Lysosomes were destabilized using the lysosomotropic agent L-leucyl-L-leucine methyl ester (Leu-Leu-OMe). Active caspase-1 was detected using FAM-YVAD-FMK, a fluorescent-labeled inhibitor of caspases (FLICA) specific for caspase-1. IL-1β was detected by immunoblotting and ELISA, and cytotoxicity was evaluated by LDH quantification.

resultsRPE of eyes affected by geographic atrophy or neovascular AMD exhibited NLRP3 staining at lesion sites. ARPE-19 cells were found to express NLRP3, ASC, and procaspase-1. IL-1α dose-dependently induced pro-IL-1β expression in ARPE-19 cells. Lysosomal destabilization induced by Leu-Leu-OMe triggered caspase-1 activation, IL-1β secretion, and ARPE-19 cell death. Blocking Leu-Leu-OMe-induced lysosomal disruption with the compound Gly-Phe-CHN(2) or inhibiting caspase-1 with Z-YVAD-FMK abrogated IL-1β release and ARPE-19 cytotoxicity.

conclusionsNLRP3 upregulation occurs in the RPE during the pathogenesis of advanced AMD, in both geographic atrophy and neovascular AMD. Destabilization of RPE lysosomes induces NLRP3 inflammasome activation, which may contribute to AMD pathology through the release of the proinflammatory cytokine IL-1β and through caspase-1-mediated cell death, known as "pyroptosis."

Indexed as

Macular DegenerationRetinal Pigment EpitheliumCarrier ProteinsCaspase 1Cell DeathHEK293 CellsHumansInflammasomesInterleukin-1betaLysosomesNF-kappa BNLR Family, Pyrin Domain-Containing 3 ProteinOptic Disk DrusenRNA, Small InterferingCarrier ProteinsCaspase 1InflammasomesInterleukin-1betaNF-kappa BNLR Family, Pyrin Domain-Containing 3 ProteinNLRP3 protein, humanRNA, Small Interfering

Identifiers

PMID23221073
PMCPMC3544415
OpenAlexW2059563381

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

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.