Amyloid Fibrils Trigger the Release of Neutrophil Extracellular Traps (NETs), Causing Fibril Fragmentation by NET-associated Elastase

The accumulation of amyloid fibrils is a feature of amyloid diseases, where cell toxicity is due to soluble oligomeric species that precede fibril formation or are formed by fibril fragmentation, but the mechanism(s) of fragmentation is still unclear. Neutrophil-derived elastase and histones were fo...

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Bibliographic Details
Published in:The Journal of biological chemistry 2012-10, Vol.287 (44), p.37206-37218
Main Authors: Azevedo, Estefania P.C., Guimarães-Costa, Anderson B., Torezani, Guilherme S., Braga, Carolina A., Palhano, Fernando L., Kelly, Jeffery W., Saraiva, Elvira M., Foguel, Debora
Format: Article
Language:English
Subjects:
Acetophenones - pharmacology
Aggregation
alpha-Synuclein - chemistry
alpha-Synuclein - genetics
alpha-Synuclein - physiology
Amyloid
Amyloid - chemistry
Amyloid - genetics
Amyloid - physiology
Amyloid Neuropathies, Familial - enzymology
Amyloid Neuropathies, Familial - genetics
Amyloid Neuropathies, Familial - pathology
Amyloidosis - enzymology
Amyloidosis - metabolism
Amyloidosis - pathology
Animals
Biomarkers - metabolism
Cell Nucleus - metabolism
Cell Survival - drug effects
Chromatin - enzymology
Chromatin - metabolism
Cricetinae
Extracellular Space - enzymology
Extracellular Space - metabolism
Hep G2 Cells
Humans
Immunoglobulin Light-chain Amyloidosis
Innate Immunity
Lung - enzymology
Lung - metabolism
Lung - pathology
Molecular Bases of Disease
Mutation, Missense
NADPH Oxidases - antagonists & inhibitors
NADPH Oxidases - metabolism
Neutrophil
Neutrophil Extracellular Trap
Neutrophils - enzymology
Neutrophils - metabolism
Neutrophils - pathology
Onium Compounds - pharmacology
Pancreatic Elastase
Peptide Fragments - metabolism
Peptide Fragments - pharmacology
Peptide Fragments - physiology
Prealbumin - chemistry
Prealbumin - genetics
Prealbumin - physiology
Protein Structure, Quaternary
Proteolysis
Reactive Oxygen Species - metabolism
Skin - enzymology
Skin - metabolism
Skin - pathology
Toxic Oligomers
α-Synuclein
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Summary:The accumulation of amyloid fibrils is a feature of amyloid diseases, where cell toxicity is due to soluble oligomeric species that precede fibril formation or are formed by fibril fragmentation, but the mechanism(s) of fragmentation is still unclear. Neutrophil-derived elastase and histones were found in amyloid deposits from patients with different systemic amyloidoses. Neutrophil extracellular traps (NETs) are key players in a death mechanism in which neutrophils release DNA traps decorated with proteins such as elastase and histones to entangle pathogens. Here, we asked whether NETs are triggered by amyloid fibrils, reasoning that because proteases are present in NETs, protease digestion of amyloid may generate soluble, cytotoxic species. We show that amyloid fibrils from three different sources (α-synuclein, Sup35, and transthyretin) induced NADPH oxidase-dependent NETs in vitro from human neutrophils. Surprisingly, NET-associated elastase digested amyloid fibrils into short species that were cytotoxic for BHK-21 and HepG2 cells. In tissue sections from patients with primary amyloidosis, we also observed the co-localization of NETs with amyloid deposits as well as with oligomers, which are probably derived from elastase-induced fibril degradation (amyloidolysis). These data reveal that release of NETs, so far described to be elicited by pathogens, can also be triggered by amyloid fibrils. Moreover, the involvement of NETs in amyloidoses might be crucial for the production of toxic species derived from fibril fragmentation. Background: Amyloid fibrils are ubiquitous structures present in amyloid diseases, but the mechanism by which they exert toxicity is unclear. Results: Neutrophil-derived extracellular DNA traps decorated with elastase are present in amyloidotic human tissue and induce amyloid fragmentation into toxic oligomers. Conclusion: Neutrophil-derived elastase participates in amyloid fragmentation (amyloidolysis). Significance: Understanding how amyloid exerts toxicity is important for the design of therapies for incurable, mostly fatal, amyloid diseases.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M112.369942