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Immunoregulation of Neutrophil Extracellular Trap Formation by Endothelial-Derived p33 (gC1q Receptor)

Neumann, Ariane LU ; Papareddy, Praveen LU ; Westman, Johannes LU ; Hyldegaard, Ole; Snäll, Johanna; Norrby-Teglund, Anna and Herwald, Heiko LU (2018) In Journal of Innate Immunity 10(1). p.30-43
Abstract

The formation of neutrophil extracellular traps (NETs) is a host defence mechanism, known to facilitate the entrapment and growth inhibition of many bacterial pathogens. It has been implicated that the translocation of myeloperoxidase (MPO) from neutrophilic granules to the nucleus is crucial to this process. Under disease conditions, however, excessive NET formation can trigger self-destructive complications by releasing pathologic levels of danger-associated molecular pattern molecules (DAMPs). To counteract such devastating immune reactions, the host has to rely on precautions that help circumvent these deleterious effects. Though the induction of DAMP responses has been intensively studied, the mechanisms that are used by the host... (More)

The formation of neutrophil extracellular traps (NETs) is a host defence mechanism, known to facilitate the entrapment and growth inhibition of many bacterial pathogens. It has been implicated that the translocation of myeloperoxidase (MPO) from neutrophilic granules to the nucleus is crucial to this process. Under disease conditions, however, excessive NET formation can trigger self-destructive complications by releasing pathologic levels of danger-associated molecular pattern molecules (DAMPs). To counteract such devastating immune reactions, the host has to rely on precautions that help circumvent these deleterious effects. Though the induction of DAMP responses has been intensively studied, the mechanisms that are used by the host to down-regulate them are still not understood. In this study, we show that p33 is an endothelial-derived protein that has the ability to annul NET formation. We found that the expression of human p33 is up-regulated in endothelial cells upon infections with Streptococcus pyogenes bacteria. Using tissue biopsies from a patient with streptococcal necrotising fasciitis, we monitored co-localisation of p33 with MPO. Further in vitro studies revealed that p33 is able to block the formation of DAMP-induced NET formation by inhibiting the enzymatic activity of MPO. Additionally, mice challenged with S. pyogenes bacteria demonstrated diminished MPO activity when treated with p33. Together, our results demonstrate that host-derived p33 has an important immunomodulating function that helps to counterbalance an overwhelming DAMP response.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
<italic>Streptococcus pyogenes</italic> infection, Danger-associated molecular pattern molecules, Innate immunity, Neutrophil extracellular traps
in
Journal of Innate Immunity
volume
10
issue
1
pages
30 - 43
publisher
Karger
external identifiers
  • scopus:85031804276
ISSN
1662-811X
DOI
10.1159/000480386
language
English
LU publication?
yes
id
91090879-1109-411a-b623-1bee822e5d38
date added to LUP
2017-11-08 09:31:33
date last changed
2018-02-18 05:05:16
@article{91090879-1109-411a-b623-1bee822e5d38,
  abstract     = {<p>The formation of neutrophil extracellular traps (NETs) is a host defence mechanism, known to facilitate the entrapment and growth inhibition of many bacterial pathogens. It has been implicated that the translocation of myeloperoxidase (MPO) from neutrophilic granules to the nucleus is crucial to this process. Under disease conditions, however, excessive NET formation can trigger self-destructive complications by releasing pathologic levels of danger-associated molecular pattern molecules (DAMPs). To counteract such devastating immune reactions, the host has to rely on precautions that help circumvent these deleterious effects. Though the induction of DAMP responses has been intensively studied, the mechanisms that are used by the host to down-regulate them are still not understood. In this study, we show that p33 is an endothelial-derived protein that has the ability to annul NET formation. We found that the expression of human p33 is up-regulated in endothelial cells upon infections with Streptococcus pyogenes bacteria. Using tissue biopsies from a patient with streptococcal necrotising fasciitis, we monitored co-localisation of p33 with MPO. Further in vitro studies revealed that p33 is able to block the formation of DAMP-induced NET formation by inhibiting the enzymatic activity of MPO. Additionally, mice challenged with S. pyogenes bacteria demonstrated diminished MPO activity when treated with p33. Together, our results demonstrate that host-derived p33 has an important immunomodulating function that helps to counterbalance an overwhelming DAMP response.</p>},
  author       = {Neumann, Ariane and Papareddy, Praveen and Westman, Johannes and Hyldegaard, Ole and Snäll, Johanna and Norrby-Teglund, Anna and Herwald, Heiko},
  issn         = {1662-811X},
  keyword      = {<italic>Streptococcus pyogenes</italic> infection,Danger-associated molecular pattern molecules,Innate immunity,Neutrophil extracellular traps},
  language     = {eng},
  number       = {1},
  pages        = {30--43},
  publisher    = {Karger},
  series       = {Journal of Innate Immunity},
  title        = {Immunoregulation of Neutrophil Extracellular Trap Formation by Endothelial-Derived p33 (gC1q Receptor)},
  url          = {http://dx.doi.org/10.1159/000480386},
  volume       = {10},
  year         = {2018},
}