Journal of inflammation research · 2026
Neutrophil Extracellular Traps Mediate in vitro and in vivo Degradation of α-Synuclein Amyloid Fibrils.
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Cardim-Pires Thyago R, Martins Ariele da Silva, Guimarães Fernanda Verdini, De Mattos Thayana Roberta Ferreira, Lepinay Eva, Saint-Pierre Martine, Cicchetti Francesca, Saraiva Elvira M, Silva Patrícia Machado Rodrigues, Foguel Debora
Аннотация
PURPOSE: Neutrophil extracellular traps (NETs) are chromatin-based structures decorated with neutrophil enzymes such as elastase and myeloperoxidase (MPO). We previously demonstrated that amyloid fibrils (AFs), regardless of their protein composition, induce NET release in human neutrophils in vitro through a mechanism dependent on reactive oxygen species generated by NADPH oxidase 2 (NOX2). In this study, we investigated whether α-synuclein amyloid fibrils (αSF) induce NET formation in vivo and whether NETs modulate amyloid-associated pathology.
METHODS: αSF were instilled intratracheally into wild-type (WT) and gp91phox knockout (KO) mice, which lack NOX-2 activity and are unable to form NETs. Both male and female mice were analyzed. Eight hours post-instillation, lungs were assessed for neutrophil infiltration, NET formation (citrullinated histones and myeloperoxidase), amyloid fibril persistence (Congo red staining), and lung mechanics (elastance and resistance).
RESULTS: αSF induced robust neutrophil recruitment and lung inflammation in both WT and KO mice. However, NET formation was detected exclusively in WT animals. Congo red-positive amyloid-like structures persisted in KO lungs but were largely absent in WT mice, indicating NET-associated proteolysis promotes fibril clearance. Functionally, αSF impaired lung elastance in both genotypes at early time points. As fibrils were cleared in WT mice, lung function recovered. In contrast, KO animals exhibited persistent fibril deposition and sustained elastance impairment. Additionally, NET structures were observed in post-mortem brain tissue from patients with Parkinson's disease.
CONCLUSION: These findings demonstrate that NETs act as an innate immune mechanism capable of sensing and degrading amyloid fibrils in vivo, thereby promoting their clearance and preserving tissue function. This mechanism may play a relevant role in modulating amyloid-associated pathology, including in human neurodegenerative diseases such as Parkinson's disease.
METHODS: αSF were instilled intratracheally into wild-type (WT) and gp91phox knockout (KO) mice, which lack NOX-2 activity and are unable to form NETs. Both male and female mice were analyzed. Eight hours post-instillation, lungs were assessed for neutrophil infiltration, NET formation (citrullinated histones and myeloperoxidase), amyloid fibril persistence (Congo red staining), and lung mechanics (elastance and resistance).
RESULTS: αSF induced robust neutrophil recruitment and lung inflammation in both WT and KO mice. However, NET formation was detected exclusively in WT animals. Congo red-positive amyloid-like structures persisted in KO lungs but were largely absent in WT mice, indicating NET-associated proteolysis promotes fibril clearance. Functionally, αSF impaired lung elastance in both genotypes at early time points. As fibrils were cleared in WT mice, lung function recovered. In contrast, KO animals exhibited persistent fibril deposition and sustained elastance impairment. Additionally, NET structures were observed in post-mortem brain tissue from patients with Parkinson's disease.
CONCLUSION: These findings demonstrate that NETs act as an innate immune mechanism capable of sensing and degrading amyloid fibrils in vivo, thereby promoting their clearance and preserving tissue function. This mechanism may play a relevant role in modulating amyloid-associated pathology, including in human neurodegenerative diseases such as Parkinson's disease.