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On Generation and Function of Neutrophil Extracellular Traps in Abdominal Sepsis

Hawez, Avin LU (2020) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
Abstract
Sepsis is a clinical condition that develops when the immune system over-response to an infection. Sepsis can lead to organ failure as well as subsequent death. Sepsis-induced host response involves neutrophil over activation which can lead to self tissue damage. Neutrophils are the first line of defence, play a critical role in controlling the infection. Upon activation, neutrophils release neutrophil extracellular traps (NETs) as part of the host defence. NETs can be harmful in a certain conditions and involved in the pathogenesis of inflammatory diseases. The underlying mechanisms of NET formation in abdominal sepsis is still scarce. Thus, to understand the signaling mechanism of NET formation and it’s role in abdominal... (More)
Abstract
Sepsis is a clinical condition that develops when the immune system over-response to an infection. Sepsis can lead to organ failure as well as subsequent death. Sepsis-induced host response involves neutrophil over activation which can lead to self tissue damage. Neutrophils are the first line of defence, play a critical role in controlling the infection. Upon activation, neutrophils release neutrophil extracellular traps (NETs) as part of the host defence. NETs can be harmful in a certain conditions and involved in the pathogenesis of inflammatory diseases. The underlying mechanisms of NET formation in abdominal sepsis is still scarce. Thus, to understand the signaling mechanism of NET formation and it’s role in abdominal sepsis, we investigated the role of c-Abl kinase in paper I. We detected NETs by electron microscopy in the lungs of septic mice. We found that inhibition of c-Abl kinase decreased CXC chemokines, neutrophil recruitment, and tissue injury in the lung. As well as it reduced plasma levels of DNA-histone complex in septic mice. In paper II, we show that miR-155 positively regulates neutrophil expression of peptidylarginine deiminase 4 (PAD4) which catalyzes histone hypercitrullination as part of NET formation. Bone marrow neutrophils were transfected with a mimic miR-155 which increased PAD4 expression and NET formation, while neutrophils transfected with antagomiR-155 decreased PAD4 expression and NET formation. In paper III, we studied the role of miR-155 in regulating NET formation in a mouse model of abdominal sepsis. In miR-155 deficient cecal ligation and puncture mice, we observed a reduction of CXC chemokines and neutrophil recruitment. In paper IV, by use of intravital microscopy, we observed that NET-microparticle aggregates participate in neutrophils-endothelium interactions. We found that neutrophil recruitment is mediated by HMGB-1 expressed on MPs via TLR2 and TLR4 signalling. Taken together our findings in the current thesis identified mechanisms of NET formation and tissue damage in abdominal sepsis. Thus, targeting these specific mechanisms of NET generation could be a useful strategy to ameliorate lung damage in abdominal sepsis.
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author
supervisor
opponent
  • Professor Boros, Mihály, Institute of Surgical Research, University of Szeged, Hungary
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Abdominal sepsis, inflamation, neutrophil, neutrophil extracellular traps, mRNA, adhesion.
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2020:116
pages
78 pages
publisher
Lund University, Faculty of Medicine
defense location
Kirurgiska kliniken, rum 3050, våning 3, Carl-Bertil Laurells gata 9, Skånes Universitetssjukhus i Malmö
defense date
2020-11-02 09:00:00
ISSN
1652-8220
ISBN
978-91-7619-979-4
language
English
LU publication?
yes
id
3d8b6653-7062-47f2-842c-daf05b0cb7ac
date added to LUP
2020-10-10 13:57:27
date last changed
2020-10-15 09:21:42
@phdthesis{3d8b6653-7062-47f2-842c-daf05b0cb7ac,
  abstract     = {Abstract<br/>Sepsis is a clinical condition that develops when the immune system over-response to an infection. Sepsis can lead to organ failure as well as subsequent death. Sepsis-induced host response involves neutrophil over activation which can lead to self tissue damage. Neutrophils are the first line of defence, play a critical role in controlling the infection. Upon activation, neutrophils release neutrophil extracellular traps (NETs) as part of the host defence. NETs can be harmful in a certain conditions and involved in the pathogenesis of inflammatory diseases. The underlying mechanisms of NET formation in abdominal sepsis is still scarce. Thus, to understand the signaling mechanism of NET formation and it’s role in abdominal sepsis, we investigated the role of c-Abl kinase in paper I. We detected NETs by electron microscopy in the lungs of septic mice. We found that inhibition of c-Abl kinase decreased CXC chemokines, neutrophil recruitment, and tissue injury in the lung. As well as it reduced plasma levels of DNA-histone complex in septic mice. In paper II, we show that miR-155 positively regulates neutrophil expression of peptidylarginine deiminase 4 (PAD4) which catalyzes histone hypercitrullination as part of NET formation. Bone marrow neutrophils were transfected with a mimic miR-155 which increased PAD4 expression and NET formation, while neutrophils transfected with antagomiR-155 decreased PAD4 expression and NET formation. In paper III, we studied the role of miR-155 in regulating NET formation in a mouse model of abdominal sepsis. In miR-155 deficient cecal ligation and puncture mice, we observed a reduction of CXC chemokines and neutrophil recruitment. In paper IV, by use of intravital microscopy, we observed that NET-microparticle aggregates participate in neutrophils-endothelium interactions. We found that neutrophil recruitment is mediated by HMGB-1 expressed on MPs via TLR2 and TLR4 signalling. Taken together our findings in the current thesis identified mechanisms of NET formation and tissue damage in abdominal sepsis. Thus, targeting these specific mechanisms of NET generation could be a useful strategy to ameliorate lung damage in abdominal sepsis.<br/>},
  author       = {Hawez, Avin},
  isbn         = {978-91-7619-979-4},
  issn         = {1652-8220},
  language     = {eng},
  number       = {2020:116},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {On Generation and Function of Neutrophil Extracellular Traps in Abdominal Sepsis},
  url          = {https://lup.lub.lu.se/search/ws/files/85377294/Avin_Hawez_Thesis_PDF_version.pdf},
  year         = {2020},
}