Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps

Papayannopoulos, Venizelos; Metzler, Kathleen D.; Hakkim, Abdul; Zychlinsky, Arturo

doi:10.1083/jcb.201006052

Cited by 1,609 publications

(1,398 citation statements)

References 77 publications

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“…Results obtained in PMNE knock-out mice showed that these animals do not form NETs in a pulmonary model of bacterial infection [24]. These and other studies [24] collectively demonstrated that PMNE is essential for the initiation of NET formation and is externalized together with NETs after stimulation of neutrophils. Therefore, based on our results we conclude that the increased PMNE levels in acute TTP may originate from neutrophils in a process of cell activation and NET release.…”

Section: Discussionmentioning

confidence: 81%

“…NET is formed by a DNA-histones scaffold that contains granule proteins such as elastase and myeloperoxidase, as well as antimicrobial peptides [23]. Results obtained in PMNE knock-out mice showed that these animals do not form NETs in a pulmonary model of bacterial infection [24]. These and other studies [24] collectively demonstrated that PMNE is essential for the initiation of NET formation and is externalized together with NETs after stimulation of neutrophils.…”

Section: Discussionmentioning

confidence: 92%

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Elevated plasma neutrophil elastase concentration is associated with disease activity in patients with thrombotic thrombocytopenic purpura

Mikes

Sinkovits

Farkas

et al. 2014

Thrombosis Research

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Keywords:Polymorphonuclear leukocyte neutrophil granulocyte elastase thrombotic thrombocytopenic purpura disease activity complement activation Introduction: Genetic and autoimmune risk factors contribute to the development of thrombotic thrombocytopenic purpura (TTP) but triggers are needed to bring about acute disease. The aim of the study was to investigate the association of neutrophil activation with acute TTP, to assess whether neutrophil activation changes during plasma exchange therapy and to show if complement-and neutrophil activation are parallel, characteristic processes in acute TTP. Materials and Methods: Altogether 49 EDTA-plasma samples of 21 TTP patients with acute disease and 17 in remission were investigated along with 20 healthy controls. A stable complex of PMNE-proteinase-inhibitor was measured by ELISA (Calbiochem, Merck-Millipore, Darmstadt, Germany). Results: Acute disease was associated with significantly increased PMNE levels, the group medians were similarly low in TTP patients in remission and in healthy controls. Increased PMNE levels were characteristic for hematologically active and ADAMTS13 deficient form of TTP. PMNE concentration inversely correlated to disease activity markers platelet count (r = − 0.349, p = 0.032) and hemoglobin levels (p = − 0.382 p = 0.018). Achievement of remission was associated with significant reduction of plasma PMNE levels (p = 0.031, Wilcoxon test). There was positive correlation between PMNE levels and complement activation markers C3a and Bb. Conclusions: We report increased PMNE levels in acute TTP and showed its association to activity markers of acute TTP and complement activation. Effective treatment of an acute TTP episode resulted in marked decrease in PMNE levels. Our data support and extend previous observations that neutrophil extracellular traps may be released in acute TTP and potentially contribute to the pathophysiology of this disease.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 92%

Elevated plasma neutrophil elastase concentration is associated with disease activity in patients with thrombotic thrombocytopenic purpura

Mikes

Sinkovits

Farkas

et al. 2014

Thrombosis Research

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“…Neutrophil azoruphilic granules contain neutrophil elastase (NE), proteinase 3 (PR3) and cathepsin G (CG); however, only NE is translocated to the nucleus and neither inhibition of PR3 nor CG can prevent this translocation 7. Furthermore, the process does not appear to be mediated by fusion of granules with the nucleus, but rather NE dissociates from the granular membrane in a ROS‐dependent manner, before degrading cytosolic actin, arresting actin dynamics and translocating across the nuclear membrane using specific translocation mechanisms 67.…”

Section: Histone Processing and Active Release During Netosismentioning

confidence: 99%

“…Binding of nucleic acid by proteases initiates a process of degradation of nuclear binding proteins68 and controlled integration of MPO into the forming NET. Nuclear NE leads to early degradation of linker histone H1, followed by core histone H4 which coincides with nuclear chromatin decondensation 7. Histone H3 appears to be resistant to degradation in intact nuclei, but not in purified form, suggesting one of the purposes of post‐translational modification is to render histone H3 resistant to NE‐related degradation.…”

Section: Histone Processing and Active Release During Netosismentioning

confidence: 99%

“…In normal cell function, these alter the nature of the histone‐DNA interaction and allow transcription to occur. More recently, controlled histone degradation has been described in neutrophils leading to chromatin decondensation and release of genomic DNA laced with granular proteins as neutrophil extracellular traps (NETs) 6, 7. These meshwork‐like structures promote intravascular thrombosis,8 limit spread of microorganisms, encourage cancer metastasis9 and cause direct injury to adjacent cells 10…”

Section: Introductionmentioning

confidence: 99%

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Biology, role and therapeutic potential of circulating histones in acute inflammatory disorders

Szatmary

Huang

Criddle

et al. 2018

J Cellular Molecular Medi

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Histones are positively charged nuclear proteins that facilitate packaging of DNA into nucleosomes common to all eukaryotic cells. Upon cell injury or cell signalling processes, histones are released passively through cell necrosis or actively from immune cells as part of extracellular traps. Extracellular histones function as microbicidal proteins and are pro‐thrombotic, limiting spread of infection or isolating areas of injury to allow for immune cell infiltration, clearance of infection and initiation of tissue regeneration and repair. Histone toxicity, however, is not specific to microbes and contributes to tissue and end‐organ injury, which in cases of systemic inflammation may lead to organ failure and death. This review details the processes of histones release in acute inflammation, the mechanisms of histone‐related tissue toxicity and current and future strategies for therapy targeting histones in acute inflammatory diseases.

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The complement system in Aspergillus fumigatus infections and its crosstalk with pentraxins

et al. 2020

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Aspergillosis is a life-threatening infection mostly affecting immunocompromised individuals and primarily caused by the saprophytic fungus Aspergillus fumigatus. At the host-pathogen interface, both cellular and humoral components of the innate immune system are increasingly acknowledged as essential players in the recognition and disposal of this opportunistic mold. Fundamental hereof is the contribution of the complement system, which deploys all three activation pathways in the battle against A. fumigatus, and functionally cooperates with other soluble pattern recognition molecules, including pentraxins. In particular, preclinical and clinical observations point to the long pentraxin PTX3 as a nonredundant and complement-dependent effector with protective functions against A. fumigatus.Based on past and current literature, here we discuss how the complement participates in the immune response to this fungal pathogen, and illustrate its crosstalk with the pentraxins, with a focus on PTX3. Emphasis is placed on the molecular mechanisms underlying such processes, the genetic evidence from human epidemiology, and the translational potential of the currently available knowledge.Aspergillus fumigatus is an evolutionary ancient filamentous fungus (mold) that flourishes in soil and decomposing vegetation [1]. Traditionally regarded as asexual, the life cycle of this ubiquitous saprophyte actually comprises cryptic forms of sexual reproduction [2] and is hallmarked by several morphotypes with distinct metabolic, compositional, and structural traits [3]. The metabolically inactive and asexual airborne spores (known as dormant or resting conidia) are encased in a robust cell wall mostly made of complex polysaccharides [i.e., aand b-glucans, chitin, galactomannan (GM), and galactosaminogalactan (GAG)] in addition to lipids, proteins, and melanin pigments [i.e., dihydroxynaphthalene (DHN) melanin] [4]. Small in size (i.e., 2-3 µm across) and enveloped in a layer of hydrophobic rodlet-like proteins (i.e.

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Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps

Abstract: Neutrophil elastase escapes azurophilic granules, translocates to the nucleus, and degrades histones to promote chromatin decondensation necessary for NET formation.

Cited by 1,609 publications

References 77 publications

Elevated plasma neutrophil elastase concentration is associated with disease activity in patients with thrombotic thrombocytopenic purpura

Elevated plasma neutrophil elastase concentration is associated with disease activity in patients with thrombotic thrombocytopenic purpura

Biology, role and therapeutic potential of circulating histones in acute inflammatory disorders

The complement system in Aspergillus fumigatus infections and its crosstalk with pentraxins

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