Journal Article

DZNE-2020-06938

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Efficacy of novel selective NLRP3 inhibitors in human and murine retinal pigment epithelial cells.

Wang, L. ; Schmidt, S. ; Larsen, P. P. ; Meyer, J. H. ; Roush, W. R. ; Latz, E.DZNE* ; Holz, F. G. ; Krohne, T. U. (Corresponding author)

2019
Springer New York, NY

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Please use a persistent id in citations: doi:10.1007/s00109-019-01753-5

Abstract: NLRP3 inflammasome activation in the retinal pigment epithelium (RPE) is observed in atrophic age-related macular degeneration (AMD), and pharmacological NLRP3 inhibition may provide a therapeutic strategy to halt disease progression. We tested selective NLRP3 inhibitors (IFM-514, IFM-632, and CRID3) for their efficacy in human and murine RPE cells. Inflammasome activation was induced in primary human RPE cells and ARPE-19 cells following priming with IL-1α by different stimuli, including lysosomal membrane permeabilization by leucyl-leucine methyl ester (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, and P2X7 receptor activation by benzoylbenzoyl-ATP. Independent of the applied activation mechanism, treatment with the NLRP3 inhibitors IFM-632, IFM-514, and CRID3 resulted in a significant suppression of inflammasome activation as assessed by IL-1β and LDH release. Likewise, inflammasome activation in blue light-irradiated Abca4-/- mouse and Leu-Leu-OMe-treated wild-type mouse RPE/choroid/sclera eye cups was significantly reduced by treatment with the NLRP3 inhibitors. These results indicate that the investigated selective NLRP3 inhibitors are effective in human and murine RPE cells, thus representing promising agents for the future evaluation of inflammasome inhibition as a therapeutic strategy in atrophic AMD. KEY MESSAGES: • NLRP3 inhibitors suppress inflammasome activation in human RPE cells independent of trigger. • Light-induced inflammasome activation in Abca4-/- mouse eye cups is reduced by NLRP3 inhibitors. • Novel selective NLRP3 inhibitors are effective in human and murine RPE cells. • Promising compounds for pharmaceutical intervention in atrophic AMD.

Keyword(s): Animals (MeSH) ; Cell Line (MeSH) ; Cells, Cultured (MeSH) ; Drug Discovery (MeSH) ; Humans (MeSH) ; Inflammasomes: antagonists & inhibitors (MeSH) ; Inflammasomes: metabolism (MeSH) ; Macular Degeneration: drug therapy (MeSH) ; Macular Degeneration: metabolism (MeSH) ; Mice (MeSH) ; NLR Family, Pyrin Domain-Containing 3 Protein: antagonists & inhibitors (MeSH) ; NLR Family, Pyrin Domain-Containing 3 Protein: metabolism (MeSH) ; Retinal Pigment Epithelium: cytology (MeSH) ; Retinal Pigment Epithelium: drug effects (MeSH) ; Retinal Pigment Epithelium: metabolism (MeSH)

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Contributing Institute(s):

1. Innate Immunity in Neurodegeneration (AG Latz ; AG Latz)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2019

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 5 ; JCR ; SCOPUS ; Web of Science Core Collection

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