Light induces NLRP3 inflammasome activation in retinal pigment epithelial cells via lipofuscin-mediated photooxidative damage
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| 024 | 7 | 0 | |a 10.1007/s00109-015-1275-1 |2 doi |
| 035 | |a (NATIONALLICENCE)springer-10.1007/s00109-015-1275-1 | ||
| 245 | 0 | 0 | |a Light induces NLRP3 inflammasome activation in retinal pigment epithelial cells via lipofuscin-mediated photooxidative damage |h [Elektronische Daten] |c [Carolina Brandstetter, Lena Mohr, Eicke Latz, Frank Holz, Tim Krohne] |
| 520 | 3 | |a Photooxidative damage and chronic innate immune activation have been implicated in retinal pigment epithelium (RPE) dysfunction, a process that underlies blinding diseases such as age-related macular degeneration (AMD). To identify a potential molecular link between these mechanisms, we investigated whether lipofuscin-mediated phototoxicity activates the NLRP3 inflammasome in RPE cells in vitro. We found that blue light irradiation (dominant wavelength 448nm, irradiance 0.8mW/cm2, duration 6h) of lipofuscin-loaded primary human RPE cells and ARPE-19 cells induced photooxidative damage, lysosomal membrane permeabilization (79.5% of cells vs. 3.8% in nonirradiated controls), and cytosolic leakage of lysosomal enzymes. This resulted in activation of the inflammasome with activation of caspase-1 and secretion of interleukin-1β (14.6 vs. 0.9pg/ml in nonirradiated controls) and interleukin-18 (87.7 vs. 0.2pg/ml in nonirradiated controls). Interleukin secretion was dependent on the activity of NLRP3, caspase-1, and lysosomal proteases cathepsin B and L. These results demonstrate that accumulation of lipofuscin-like material in vitro renders RPE cells susceptible to phototoxic destabilization of lysosomes, resulting in NLRP3 inflammasome activation and secretion of inflammatory cytokines. This new mechanism of inflammasome activation links photooxidative damage and innate immune activation in RPE pathology and may provide novel targets for therapeutic intervention in retinal diseases such as AMD. Key message: • Visible light irradiation of lipofuscin-loaded RPE cells activates inflammasome. • Inflammasome activation results from lysosomal permeabilization and enzyme leakage. • Inflammasome activation induces secretion of inflammatory cytokines by RPE cells. • Photooxidative damage by visible light as new mechanism of inflammasome activation. • Novel link between hallmark pathogenetic features of retinal degenerative diseases. | |
| 540 | |a The Author(s), 2015 | ||
| 690 | 7 | |a Age-related macular degeneration |2 nationallicence | |
| 690 | 7 | |a Retinal pigment epithelium |2 nationallicence | |
| 690 | 7 | |a Interleukin-1β |2 nationallicence | |
| 690 | 7 | |a Lysosomal membrane permeabilization |2 nationallicence | |
| 690 | 7 | |a Lipid peroxidation |2 nationallicence | |
| 690 | 7 | |a A2E : N-retinylidene-N-retinyl-ethanolamine |2 nationallicence | |
| 690 | 7 | |a AMD : Age-related macular degeneration |2 nationallicence | |
| 690 | 7 | |a ASC : Apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD) |2 nationallicence | |
| 690 | 7 | |a CEP : Carboxyethylpyrrole |2 nationallicence | |
| 690 | 7 | |a DABCO : 1,4-Diazabicyclooctane |2 nationallicence | |
| 690 | 7 | |a FAM-YVAD-FMK : Carboxyfluorescein-Tyr-Val-Ala-Asp-fluoromethylketone |2 nationallicence | |
| 690 | 7 | |a FLICA : Fluorochrome-labeled inhibitor of caspases |2 nationallicence | |
| 690 | 7 | |a HNE : 4-Hydroxynonenal |2 nationallicence | |
| 690 | 7 | |a IL : Interleukin |2 nationallicence | |
| 690 | 7 | |a Leu-Leu-OMe : L-leucyl-L-leucine methyl ester |2 nationallicence | |
| 690 | 7 | |a LPS : Lipopolysaccharide |2 nationallicence | |
| 690 | 7 | |a MDA : Malondialdehyde |2 nationallicence | |
| 690 | 7 | |a NLRP3 : Nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family, pyrin domain-containing protein 3 |2 nationallicence | |
| 690 | 7 | |a POS : Photoreceptor outer segments |2 nationallicence | |
| 690 | 7 | |a RPE : Retinal pigment epithelium |2 nationallicence | |
| 690 | 7 | |a Z-FF-FMK : Z-Phe-Phe-fluoromethylketone |2 nationallicence | |
| 690 | 7 | |a Z-YVAD-FMK : Z-Tyr-Val-Ala-Asp-fluoromethylketone |2 nationallicence | |
| 700 | 1 | |a Brandstetter |D Carolina |u Department of Ophthalmology, University of Bonn, Ernst-Abbe-Str. 2, 53127, Bonn, Germany |4 aut | |
| 700 | 1 | |a Mohr |D Lena |u Department of Ophthalmology, University of Bonn, Ernst-Abbe-Str. 2, 53127, Bonn, Germany |4 aut | |
| 700 | 1 | |a Latz |D Eicke |u Institute of Innate Immunity, University of Bonn, Bonn, Germany |4 aut | |
| 700 | 1 | |a Holz |D Frank |u Department of Ophthalmology, University of Bonn, Ernst-Abbe-Str. 2, 53127, Bonn, Germany |4 aut | |
| 700 | 1 | |a Krohne |D Tim |u Department of Ophthalmology, University of Bonn, Ernst-Abbe-Str. 2, 53127, Bonn, Germany |4 aut | |
| 773 | 0 | |t Journal of Molecular Medicine |d Springer Berlin Heidelberg |g 93/8(2015-08-01), 905-916 |x 0946-2716 |q 93:8<905 |1 2015 |2 93 |o 109 | |
| 856 | 4 | 0 | |u https://doi.org/10.1007/s00109-015-1275-1 |q text/html |z Onlinezugriff via DOI |
| 898 | |a BK010053 |b XK010053 |c XK010000 | ||
| 900 | 7 | |a Metadata rights reserved |b Springer special CC-BY-NC licence |2 nationallicence | |
| 908 | |D 1 |a research-article |2 jats | ||
| 949 | |B NATIONALLICENCE |F NATIONALLICENCE |b NL-springer | ||
| 950 | |B NATIONALLICENCE |P 856 |E 40 |u https://doi.org/10.1007/s00109-015-1275-1 |q text/html |z Onlinezugriff via DOI | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Brandstetter |D Carolina |u Department of Ophthalmology, University of Bonn, Ernst-Abbe-Str. 2, 53127, Bonn, Germany |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Mohr |D Lena |u Department of Ophthalmology, University of Bonn, Ernst-Abbe-Str. 2, 53127, Bonn, Germany |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Latz |D Eicke |u Institute of Innate Immunity, University of Bonn, Bonn, Germany |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Holz |D Frank |u Department of Ophthalmology, University of Bonn, Ernst-Abbe-Str. 2, 53127, Bonn, Germany |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Krohne |D Tim |u Department of Ophthalmology, University of Bonn, Ernst-Abbe-Str. 2, 53127, Bonn, Germany |4 aut | ||
| 950 | |B NATIONALLICENCE |P 773 |E 0- |t Journal of Molecular Medicine |d Springer Berlin Heidelberg |g 93/8(2015-08-01), 905-916 |x 0946-2716 |q 93:8<905 |1 2015 |2 93 |o 109 | ||