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 B-2 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., Renne, T., Vieira, M. L., Muller-Esterl, W., Herwald, H., Lindbom, L.
Neutrophils engage the
kallikrein-kinin system to open up the endothelial
barrier in acute
inflammation.