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Signaling via β2 integrins triggers neutrophil-dependent alteration in endothelial barrier function

Gautam, Narinder ; Herwald, Heiko LU ; Hedqvist, Per and Lindbom, Lennart (2000) In Journal of Experimental Medicine 191(11). p.1829-1839
Abstract

Activation of polymorphonuclear leukocytes (PMNs) and adhesion to the endothelial lining is a major cause of edema formation. Although known to be dependent on the function of β2 integrins (CD11/CD18), the precise mechanisms by which adherent PMNs may impair endothelial barrier capacity remain unclear. Here, the role of transmembrane signaling by β2 integrins in PMN-induced alterations in tight junctional permeability of cultured endothelial cell (EC) monolayers was investigated. PMN activation, in the absence of proinflammatory stimuli, was accomplished through antibody cross- linking of CD11b/CD18, mimicking adhesion-dependent receptor engagement. CD18 cross-linking in PMNs added to the EC monolayer provoked a... (More)

Activation of polymorphonuclear leukocytes (PMNs) and adhesion to the endothelial lining is a major cause of edema formation. Although known to be dependent on the function of β2 integrins (CD11/CD18), the precise mechanisms by which adherent PMNs may impair endothelial barrier capacity remain unclear. Here, the role of transmembrane signaling by β2 integrins in PMN-induced alterations in tight junctional permeability of cultured endothelial cell (EC) monolayers was investigated. PMN activation, in the absence of proinflammatory stimuli, was accomplished through antibody cross- linking of CD11b/CD18, mimicking adhesion-dependent receptor engagement. CD18 cross-linking in PMNs added to the EC monolayer provoked a prompt increase in EC permeability that coincided with a rise in EC cytosolic free Ca2+ and rearrangement of actin filaments, events similar to those evoked by chemoattractant PMN activation. Cell-free supernatant obtained after CD18 cross-linking in suspended PMNs triggered an EC response indistinguishable from that induced by direct PMN activation, and caused clear-cut venular plasma leakage when added to the hamster cheek pouch in vivo preparation. The PMN-evoked EC response was specific to β2 integrin engagement inasmuch as antibody cross-linking of L-selectin or CD44 was without effect on EC function. Our data demonstrate a causal link between outside-in signaling by β2 integrins and the capacity of PMNs to induce alterations in vascular permeability, and suggest a paracrine mechanism that involves PMN-derived cationic protein(s) in the cellular crosstalk between PMNs and ECs.

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author
; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Endothelium, Inflammation, Integrin signaling, Leukocyte extravasation, Vascular permeability
in
Journal of Experimental Medicine
volume
191
issue
11
pages
1829 - 1839
publisher
Rockefeller University Press
external identifiers
  • pmid:10839800
  • scopus:0034608574
ISSN
0022-1007
DOI
10.1084/jem.191.11.1829
language
English
LU publication?
yes
id
51bed948-62d9-4c09-a7ed-aa6131dc7194
date added to LUP
2019-12-10 20:26:31
date last changed
2020-05-20 04:57:27
@article{51bed948-62d9-4c09-a7ed-aa6131dc7194,
  abstract     = {<p>Activation of polymorphonuclear leukocytes (PMNs) and adhesion to the endothelial lining is a major cause of edema formation. Although known to be dependent on the function of β<sub>2</sub> integrins (CD11/CD18), the precise mechanisms by which adherent PMNs may impair endothelial barrier capacity remain unclear. Here, the role of transmembrane signaling by β<sub>2</sub> integrins in PMN-induced alterations in tight junctional permeability of cultured endothelial cell (EC) monolayers was investigated. PMN activation, in the absence of proinflammatory stimuli, was accomplished through antibody cross- linking of CD11b/CD18, mimicking adhesion-dependent receptor engagement. CD18 cross-linking in PMNs added to the EC monolayer provoked a prompt increase in EC permeability that coincided with a rise in EC cytosolic free Ca<sup>2+</sup> and rearrangement of actin filaments, events similar to those evoked by chemoattractant PMN activation. Cell-free supernatant obtained after CD18 cross-linking in suspended PMNs triggered an EC response indistinguishable from that induced by direct PMN activation, and caused clear-cut venular plasma leakage when added to the hamster cheek pouch in vivo preparation. The PMN-evoked EC response was specific to β<sub>2</sub> integrin engagement inasmuch as antibody cross-linking of L-selectin or CD44 was without effect on EC function. Our data demonstrate a causal link between outside-in signaling by β<sub>2</sub> integrins and the capacity of PMNs to induce alterations in vascular permeability, and suggest a paracrine mechanism that involves PMN-derived cationic protein(s) in the cellular crosstalk between PMNs and ECs.</p>},
  author       = {Gautam, Narinder and Herwald, Heiko and Hedqvist, Per and Lindbom, Lennart},
  issn         = {0022-1007},
  language     = {eng},
  month        = {06},
  number       = {11},
  pages        = {1829--1839},
  publisher    = {Rockefeller University Press},
  series       = {Journal of Experimental Medicine},
  title        = {Signaling via β<sub>2</sub> integrins triggers neutrophil-dependent alteration in endothelial barrier function},
  url          = {http://dx.doi.org/10.1084/jem.191.11.1829},
  doi          = {10.1084/jem.191.11.1829},
  volume       = {191},
  year         = {2000},
}