Artikel
NLRP3 inflammasome as a therapeutic target in AMD
Suche in Medline nach
Autoren
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Tim U. Krohne
- Bonn/D
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L. Wang
- Bonn/D
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S. Schmidt
- Bonn/D
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J. Rossa
- Bonn/D
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P.P. Larsen
- Bonn/D
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J.H. Meyer
- Bonn/D
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W.R. Roush
- IFM Therapeutics, Boston/USA
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E. Latz
- IFM Therapeutics, Boston/USA; Institute of Innate Immunity, University of Bonn/D
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F.G. Holz
- Bonn/D
| Veröffentlicht: | 5. Februar 2020 |
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Gliederung
Text
Background: NLRP3 inflammasome activation in the retinal pigment epithelium (RPE) is observed in atrophic age-related macular degeneration (AMD). Pharmacological NLRP3 inhibition may provide a therapeutic strategy to halt disease progression. We tested novel selective NLRP3 inhibitors (IFM-514, IFM-632, and CRID3) for their efficacy in human and murine RPE cells.
Methods: Inflammasome activation was induced in primary human RPE cells, ARPE-19 cells, and murine RPE tissue cultures by different stimuli. For this, cells were priming with IL-1a and subsequently subjected to either lysosomal membrane permeabilisation by Leu-Leu-OMe, oxidative damage induced by hydrogen peroxide, lipofuscin-mediated photooxidative damage induced by incubation with 4-hydroxynonenal-modified photoreceptor outer segments and subsequent blue light irradiation, or P2X7 activation by BzATP. RPE/choroid/sclera eye cups from Abca4-/-, Abca4-/-/Nlrp3-/-, and wildtype mice were exposed to blue light irradiation or Leu-Leu-OMe. Inflammasome activation was assessed by means of IL-1b release, lactate dehydrogenase release, and ZO-1 staining.
Results: Independent of activation mechanism, treatment with the NLRP3 inhibitors IFM-514, IFM-632, and CRID3 resulted in a significant suppression of inflammasome activation as assessed by IL-1b and LDH release. E.g., 0.01 µM IFM-632 reduced IL-1b release induced by lysosomal permeabilisation, oxidative damage, photooxidative damage, and P2X7 activation in ARPE-19 cells to 16.6% (p=0.005), 6.9% (p=0.003), 39.4% (p=0.010), and 12.7% (p<0.001), respectively. Likewise, inflammasome activation in blue light-irradiated Abca4-/- mouse and Leu-Leu-OMe-treated wildtype mouse RPE/choroid/sclera eye cups was significantly reduced by treatment with the NLRP3 inhibitors.
Conclusion: The investigated selective NLRP3 inhibitors demonstrated efficacy in human and murine RPE cells and thus represent promising agents for the future evaluation of inflammasome inhibition as therapeutic strategy for atrophic AMD.
