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

Narinder Gautam, Heiko Herwald, Per Hedqvist, Lennart Lindbom

Research output: Contribution to journalArticlepeer-review

80 Citations (SciVal)

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 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.

Original languageEnglish
Pages (from-to)1829-1839
JournalJournal of Experimental Medicine
Volume191
Issue number11
DOIs
Publication statusPublished - 2000 Jun 5

Subject classification (UKÄ)

  • Cell and Molecular Biology

Keywords

  • Endothelium
  • Inflammation
  • Integrin signaling
  • Leukocyte extravasation
  • Vascular permeability

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