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

Research output: Contribution to journalArticle

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 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.

Details

Authors
  • Ellinor Kenne
  • Joel Rasmuson
  • Thomas Renné
  • Monica L. Vieira
  • Werner Müller-Esterl
  • Heiko Herwald
  • Lennart Lindbom
Organisations
External organisations
  • Karolinska Institutet
  • University Medical Center Hamburg-Eppendorf
  • Instituto Butantan
  • Goethe University
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology

Keywords

  • bradykinin, degranulation, leukocyte, vascular permeability
Original languageEnglish
Pages (from-to)2599-2609
Number of pages11
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume33
Issue number2
Publication statusPublished - 2019 Feb 1
Publication categoryResearch
Peer-reviewedYes