The Journal of Experimental Medicine
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Published online 30 May 2000.
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© The Rockefeller University Press, 0022-1007/2000/6/1829/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 11, June 5, 2000 1829-1840

Original Article

Signaling via ß2 Integrins Triggers Neutrophil-dependent Alteration in Endothelial Barrier Function

Narinder Gautama, Heiko Herwaldb, Per Hedqvista, and Lennart Lindboma
a Department of Physiology and Pharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden
b Department of Cell and Molecular Biology, Lund University, S-221 00 Lund, Sweden

Correspondence to: Lennart Lindbom, Department of Physiology and Pharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden. Tel:46-8-728-7207 Fax:46-8-33-20-47 E-mail:lennart.lindbom{at}fyfa.ki.se.

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 ß2 integrins (CD11/CD18), the precise mechanisms by which adherent PMNs may impair endothelial barrier capacity remain unclear. Here, the role of transmembrane signaling by ß2 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 ß2 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 ß2 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.

Key Words: inflammation, leukocyte extravasation, endothelium, vascular permeability, integrin signaling


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