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Neutrophils engage the kallikrein-kinin system to open up the endothelial barrier in acute inflammation

Kenne, Ellinor; Rasmuson, Joel; Renné, Thomas; Vieira, Monica L. LU ; Müller-Esterl, Werner; Herwald, Heiko LU and Lindbom, Lennart (2019) In FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33(2). p.2599-2609
Abstract

Neutrophil recruitment and plasma exudation are key elements in the immune response to injury or infection. Activated neutrophils stimulate opening of the endothelial barrier; however, the underlying mechanisms have remained largely unknown. In this study, we identified a pivotal role of the proinflammatory kallikrein-kinin system and consequent formation of bradykinin in neutrophil-evoked vascular leak. In mouse and hamster models of acute inflammation, inhibitors of bradykinin generation, and signaling markedly reduced plasma exudation in response to chemoattractant activation of neutrophils. The neutrophil-driven leak was likewise suppressed in mice deficient in either the bradykinin B2 receptor or factor XII (initiator of the... (More)

Neutrophil recruitment and plasma exudation are key elements in the immune response to injury or infection. Activated neutrophils stimulate opening of the endothelial barrier; however, the underlying mechanisms have remained largely unknown. In this study, we identified a pivotal role of the proinflammatory kallikrein-kinin system and consequent formation of bradykinin in neutrophil-evoked vascular leak. In mouse and hamster models of acute inflammation, inhibitors of bradykinin generation, and signaling markedly reduced plasma exudation in response to chemoattractant activation of neutrophils. The neutrophil-driven leak was likewise suppressed in mice deficient in either the bradykinin B2 receptor or factor XII (initiator of the kallikrein-kinin system). In human endothelial cell monolayers, material secreted from activated neutrophils induced cytoskeletal rearrangement, leading to paracellular gap formation in a bradykinin-dependent manner. As a mechanistic basis, we found that a neutrophil-derived heparin-binding protein (HBP/azurocidin) displaced the bradykinin precursor high-molecular-weight kininogen from endothelial cells, thereby enabling proteolytic processing of kininogen into bradykinin by neutrophil and plasma proteases. These data provide novel insight into the signaling pathway by which neutrophils open up the endothelial barrier and identify the kallikrein-kinin system as a target for therapeutic interventions in acute inflammatory reactions.-Kenne, E., Rasmuson, J., Renné, T., Vieira, M. L., Müller-Esterl, W., Herwald, H., Lindbom, L. Neutrophils engage the kallikrein-kinin system to open up the endothelial barrier in acute inflammation.

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author
organization
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type
Contribution to journal
publication status
published
subject
keywords
bradykinin, degranulation, leukocyte, vascular permeability
in
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
volume
33
issue
2
pages
11 pages
publisher
The Federation of American Societies for Experimental Biology
external identifiers
  • scopus:85061044611
ISSN
1530-6860
DOI
10.1096/fj.201801329R
language
English
LU publication?
yes
id
ba111682-c613-44e9-8322-f91b95dd4f7f
date added to LUP
2019-02-11 13:43:49
date last changed
2019-02-11 13:43:49
@article{ba111682-c613-44e9-8322-f91b95dd4f7f,
  abstract     = {<p>Neutrophil recruitment and plasma exudation are key elements in the immune response to injury or infection. Activated neutrophils stimulate opening of the endothelial barrier; however, the underlying mechanisms have remained largely unknown. In this study, we identified a pivotal role of the proinflammatory kallikrein-kinin system and consequent formation of bradykinin in neutrophil-evoked vascular leak. In mouse and hamster models of acute inflammation, inhibitors of bradykinin generation, and signaling markedly reduced plasma exudation in response to chemoattractant activation of neutrophils. The neutrophil-driven leak was likewise suppressed in mice deficient in either the bradykinin B2 receptor or factor XII (initiator of the kallikrein-kinin system). In human endothelial cell monolayers, material secreted from activated neutrophils induced cytoskeletal rearrangement, leading to paracellular gap formation in a bradykinin-dependent manner. As a mechanistic basis, we found that a neutrophil-derived heparin-binding protein (HBP/azurocidin) displaced the bradykinin precursor high-molecular-weight kininogen from endothelial cells, thereby enabling proteolytic processing of kininogen into bradykinin by neutrophil and plasma proteases. These data provide novel insight into the signaling pathway by which neutrophils open up the endothelial barrier and identify the kallikrein-kinin system as a target for therapeutic interventions in acute inflammatory reactions.-Kenne, E., Rasmuson, J., Renné, T., Vieira, M. L., Müller-Esterl, W., Herwald, H., Lindbom, L. Neutrophils engage the kallikrein-kinin system to open up the endothelial barrier in acute inflammation.</p>},
  author       = {Kenne, Ellinor and Rasmuson, Joel and Renné, Thomas and Vieira, Monica L. and Müller-Esterl, Werner and Herwald, Heiko and Lindbom, Lennart},
  issn         = {1530-6860},
  keyword      = {bradykinin,degranulation,leukocyte,vascular permeability},
  language     = {eng},
  month        = {02},
  number       = {2},
  pages        = {2599--2609},
  publisher    = {The Federation of American Societies for Experimental Biology},
  series       = {FASEB journal : official publication of the Federation of American Societies for Experimental Biology},
  title        = {Neutrophils engage the kallikrein-kinin system to open up the endothelial barrier in acute inflammation},
  url          = {http://dx.doi.org/10.1096/fj.201801329R},
  volume       = {33},
  year         = {2019},
}