Herrera-García, Ada María;
Domínguez-Luis, María Jesús;
Arce-Franco, María;
Armas-González, Estefanía;
Álvarez de La Rosa, Diego;
Machado, José David;
Pec, Martina K.;
Feria, Manuel;
Barreiro, Olga;
Sánchez-Madrid, Francisco;
Díaz-González, Federico
Prevention of Neutrophil Extravasation by α2-Adrenoceptor–Mediated Endothelial Stabilization
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Medientyp:
E-Artikel
Titel:
Prevention of Neutrophil Extravasation by α2-Adrenoceptor–Mediated Endothelial Stabilization
Beteiligte:
Herrera-García, Ada María;
Domínguez-Luis, María Jesús;
Arce-Franco, María;
Armas-González, Estefanía;
Álvarez de La Rosa, Diego;
Machado, José David;
Pec, Martina K.;
Feria, Manuel;
Barreiro, Olga;
Sánchez-Madrid, Francisco;
Díaz-González, Federico
Erschienen:
The American Association of Immunologists, 2014
Erschienen in:
The Journal of Immunology, 193 (2014) 6, Seite 3023-3035
Sprache:
Englisch
DOI:
10.4049/jimmunol.1400255
ISSN:
0022-1767;
1550-6606
Entstehung:
Anmerkungen:
Beschreibung:
Abstract Adrenergic receptors are expressed on the surface of inflammation-mediating cells, but their potential role in the regulation of the inflammatory response is still poorly understood. The objectives of this work were to study the effects of α2-adrenergic agonists on the inflammatory response in vivo and to determine their mechanism of action. In two mouse models of inflammation, zymosan air pouch and thioglycolate-induced peritonitis models, the i.m. treatment with xylazine or UK14304, two α2-adrenergic agonists, reduced neutrophil migration by 60%. The α2-adrenergic antagonist RX821002 abrogated this effect. In flow cytometry experiments, the basal surface expression of L-selectin and CD11b was modified neither in murine nor in human neutrophils upon α2-agonist treatment. Similar experiments in HUVEC showed that UK14304 prevented the activation-dependent upregulation of ICAM-1. In contrast, UK14304 augmented electrical resistance and reduced macromolecular transport through a confluent HUVEC monolayer. In flow chamber experiments, under postcapillary venule-like flow conditions, the pretreatment of HUVECs, but not neutrophils, with α2-agonists decreased transendothelial migration, without affecting neutrophil rolling. Interestingly, α2-agonists prevented the TNF-α–mediated decrease in expression of the adherens junctional molecules, VE-cadherin, β-catenin, and plakoglobin, and reduced the ICAM-1–mediated phosphorylation of VE-cadherin by immunofluorescence and confocal analysis and Western blot analysis, respectively. These findings indicate that α2-adrenoceptors trigger signals that protect the integrity of endothelial adherens junctions during the inflammatory response, thus pointing at the vascular endothelium as a therapeutic target for the management of inflammatory processes in humans.