NET amyloidogenic backbone in human activated neutrophils

Pulze, Laura; Bassani, Barbara; Gini, Elisabetta; D’Antona, Paola; Grimaldi, Annalisa; Luini, Alessandra; Marino, Franca; Noonan, Douglas M.; Tettamanti, Gianluca; Valvassori, Roberto; Eguileor, Magda de

doi:10.1111/cei.12730

Cited by 18 publications

(14 citation statements)

References 83 publications

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“…Importantly, amyloid fibrils also accumulate in mammals, thus are evolutionary conserved [ 74 ], but their deposition mostly leads to pathological diseases such as Alzheimer disease [ 78 , 79 ]. Interestingly, amyloid fibrils can induce formation of ETs by neutrophils [ 80 ] but they also attach to neutrophil ETs where they address raptured proteins and DNA against the non-self [ 80 ].…”

Section: Discussionmentioning

confidence: 99%

Conservative Mechanisms of Extracellular Trap Formation by Annelida Eisenia andrei: Serine Protease Activity Requirement

2016

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Formation of extracellular traps (ETs) capturing and immobilizing pathogens is now a well-established defense mechanism added to the repertoire of vertebrate phagocytes. These ETs are composed of extracellular DNA (extDNA), histones and antimicrobial proteins. Formation of mouse and human ETs depends on enzymes (i) facilitating decondensation of chromatin by citrullination of histones, and (ii) serine proteases degrading histones. In invertebrates, initial reports revealed existence of ETs composed of extDNA and histones, and here we document for the first time that also coelomocytes, immunocompetent cells of an earthworm Eisenia andrei, cast ETs which successfully trap bacteria in a reactive oxygen species (ROS)-dependent and -independent manner. Importantly, the formation of ETs was observed not only when coelomocytes were studied ex vivo, but also in vivo, directly in the earthworm coelom. These ETs were composed of extDNA, heat shock proteins (HSP27) and H3 histones. Furthermore, the formation of E. andrei ETs depended on activity of serine proteases, including elastase-like activity. Moreover, ETs interconnected and hold together aggregating coelomocytes, a processes proceeding encapsulation. In conclusion, the study confirms ET formation by earthworms, and unravels mechanisms leading to ET formation and encapsulation in invertebrates.

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Section: Discussionmentioning

confidence: 99%

Conservative Mechanisms of Extracellular Trap Formation by Annelida Eisenia andrei: Serine Protease Activity Requirement

2016

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“…Amyloid fibril characterization: amyloid structures were identified according to Le Vine III [ 80 ] by staining with ThS and visualizing the amyloid-specific green/yellow fluorescence with a Leica laser confocal microscope. Amyloid fibrils were also localized immunocytochemically, using an antibody directed against Pmel17, which is one of the proteins able to form amyloid fibrillar structures in mammals [ 26 , 54 , 81 , 82 ] ( Table 1 ).…”

Section: Methodsmentioning

confidence: 99%

MCF7 Spheroid Development: New Insight about Spatio/Temporal Arrangements of TNTs, Amyloid Fibrils, Cell Connections, and Cellular Bridges

Pulze

Congiu

Brevini

et al. 2020

IJMS

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Human breast adenocarcinoma cells (MCF7) grow in three-dimensional culture as spheroids that represent the structural complexity of avascular tumors. Therefore, spheroids offer a powerful tool for studying cancer development, aggressiveness, and drug resistance. Notwithstanding the large amount of data regarding the formation of MCF7 spheroids, a detailed description of the morpho-functional changes during their aggregation and maturation is still lacking. In this study, in addition to the already established role of gap junctions, we show evidence of tunneling nanotube (TNT) formation, amyloid fibril production, and opening of large stable cellular bridges, thus reporting the sequential events leading to MCF7 spheroid formation. The variation in cell phenotypes, sustained by dynamic expression of multiple proteins, leads to complex networking among cells similar to the sequence of morphogenetic steps occurring in embryogenesis/organogenesis. On the basis of the observation that early events in spheroid formation are strictly linked to the redox homeostasis, which in turn regulate amyloidogenesis, we show that the administration of N-acetyl-l-cysteine (NAC), a reactive oxygen species (ROS) scavenger that reduces the capability of cells to produce amyloid fibrils, significantly affects their ability to aggregate. Moreover, cells aggregation events, which exploit the intrinsic adhesiveness of amyloid fibrils, significantly decrease following the administration during the early aggregation phase of neutral endopeptidase (NEP), an amyloid degrading enzyme.

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“…Amyloid structures that could be stained with Congo red and thioflavin-s were observed in activated neutrophils, and were found to colocalize with the DNA of the extracellular NET structures. The positive charge of the NET amyloid likely assists in targeting microbes, allowing it to distinguish between negatively-charged pathogen membranes and zwitterionic host membranes [65]. In addition to neutrophils, activated eosinophils, monocytes/macrophages and mast cells can secrete NETs, suggesting that amyloid bioflocculants could be an integral part of human innate immunity [66][67][68].…”

Section: Antimicrobial Properties Of Abmentioning

confidence: 99%

Alzheimer’s Amyloid-β is an Antimicrobial Peptide: A Review of the Evidence

Gosztyla

Brothers

Robinson

2018

JAD

176

173

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The amyloid-b (Ab) peptide has long been considered to be the driving force behind Alzheimer's disease (AD). However, clinical trials that have successfully reduced Ab burden in the brain have not slowed the cognitive decline, and in some instances have resulted in adverse outcomes. While these results can be interpreted in different ways, a more nuanced picture of Ab is emerging that takes into account the facts that the peptide is evolutionarily conserved and is present throughout life in cognitively normal individuals. Recent evidence indicates a role for Ab as an antimicrobial peptide (AMP), a class of innate immune defense molecule that utilizes fibrillation to protect the host from a wide range of infectious agents. In humans and in animal models, infection of the brain frequently leads to increased amyloidogenic processing of the Ab precursor protein (AbPP) and resultant fibrillary aggregates of Ab. Evidence from in vitro and in vivo studies demonstrates that Ab oligomers have potent, broad-spectrum antimicrobial properties by forming fibrils that entrap pathogens and disrupt cell membranes. Importantly, overexpression of Ab confers increased resistance to infection from both bacteria and viruses. The antimicrobial role of Ab may explain why increased rates of infection have been observed in some of the AD clinical trials that depleted Ab. Perhaps progress towards a cure for AD will accelerate once treatment strategies begin to take into account the likely physiological functions of this enigmatic peptide.

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NET amyloidogenic backbone in human activated neutrophils

Cited by 18 publications

References 83 publications

Conservative Mechanisms of Extracellular Trap Formation by Annelida Eisenia andrei: Serine Protease Activity Requirement

Conservative Mechanisms of Extracellular Trap Formation by Annelida Eisenia andrei: Serine Protease Activity Requirement

MCF7 Spheroid Development: New Insight about Spatio/Temporal Arrangements of TNTs, Amyloid Fibrils, Cell Connections, and Cellular Bridges

Alzheimer’s Amyloid-β is an Antimicrobial Peptide: A Review of the Evidence

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