Amyloid β induces NLRP3 inflammasome activation in retinal pigment epithelial cells via NADPH oxidase- and mitochondria-dependent ROS production

Ke Wang; Yong Yao; Xue Zhu; Kai Zhang; Fanfan Zhou; Ling Zhu

doi:10.1002/jbt.21887

Amyloid β induces NLRP3 inflammasome activation in retinal pigment epithelial cells via NADPH oxidase- and mitochondria-dependent ROS production

J Biochem Mol Toxicol. 2017 Jun;31(6). doi: 10.1002/jbt.21887. Epub 2016 Dec 22.

Authors

Ke Wang¹, Yong Yao², Xue Zhu¹, Kai Zhang¹, Fanfan Zhou³, Ling Zhu⁴

Affiliations

¹ Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, Jiangsu Province, People's Republic of China.
² Department of Ophthalmology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, 214023, Jiangsu Province, People's Republic of China.
³ Faculty of Pharmacy, University of Sydney, NSW, 2006, Australia.
⁴ Save Sight Institute, University of Sydney, NSW, 2000, Australia.

PMID: 28004443
DOI: 10.1002/jbt.21887

Abstract

Amyloid β (Aβ)-induced chronic inflammation is believed to be a key pathogenic process in early-stage age-related macular degeneration (AMD). Nucleotide oligomerization domain (NOD)-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation triggered by Aβ is responsible for retinal pigment epithelium (RPE) dysfunction in the onset of AMD; however, the detailed molecular mechanism remains unclear. In this study, we investigated the involvement of NADPH oxidase- and mitochondria-derived reactive oxygen species (ROS) in the process of Aβ_1-40 -induced NLRP3 inflammasome activation in LPS-primed ARPE-19 cells. The results showed that Aβ_1-40 could induce excessive ROS generation, MAPK/NF-κB signaling activation and subsequently NLRP3 inflammasome activation in LPS-primed ARPE-19 cells. Furthermore, the inductive effect of Aβ_1-40 on NLRP3 inflammasome activation was mediated in a manner dependent on NADPH oxidase- and mitochondria-derived ROS. Our findings may provide a novel insight into the molecular mechanism by which Aβ contributes to the early-stage AMD.

Keywords: NLRP3 inflammasome; age-related macular degeneration; amyloid β; reactive oxygen species.

MeSH terms

Amyloid / metabolism
Amyloid beta-Peptides / metabolism*
Cell Line
Enzyme Inhibitors / pharmacology
Humans
Inflammasomes / drug effects
Inflammasomes / immunology
Inflammasomes / metabolism*
Kinetics
Lipopolysaccharides / toxicity
MAP Kinase Signaling System / drug effects
Macular Degeneration / enzymology
Macular Degeneration / immunology
Macular Degeneration / metabolism*
Mitochondria / drug effects
Mitochondria / immunology
Mitochondria / metabolism
NADPH Oxidases / antagonists & inhibitors
NADPH Oxidases / metabolism*
NF-kappa B / agonists
NF-kappa B / antagonists & inhibitors
NF-kappa B / metabolism
NLR Family, Pyrin Domain-Containing 3 Protein / agonists*
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Oxidative Stress / drug effects
Peptide Fragments / metabolism*
Reactive Oxygen Species / agonists
Reactive Oxygen Species / antagonists & inhibitors
Reactive Oxygen Species / metabolism*
Retinal Pigment Epithelium / drug effects
Retinal Pigment Epithelium / immunology
Retinal Pigment Epithelium / metabolism*
Sulfones / pharmacology

Substances

Amyloid
Amyloid beta-Peptides
Enzyme Inhibitors
Inflammasomes
Lipopolysaccharides
NF-kappa B
NLR Family, Pyrin Domain-Containing 3 Protein
NLRP3 protein, human
Peptide Fragments
Reactive Oxygen Species
Sulfones
amyloid beta-protein (1-40)
4-(2-aminoethyl)benzenesulfonylfluoride
NADPH Oxidases