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. 2014 Sep 15;193(6):3023-35.
doi: 10.4049/jimmunol.1400255. Epub 2014 Aug 11.

Prevention of neutrophil extravasation by α2-adrenoceptor-mediated endothelial stabilization

Ada María Herrera-García  1 , María Jesús Domínguez-Luis  2 , María Arce-Franco  3 , Estefanía Armas-González  1 , Diego Álvarez de La Rosa  4 , José David Machado  5 , Martina K Pec  1 , Manuel Feria  5 , Olga Barreiro  6 , Francisco Sánchez-Madrid  7 , Federico Díaz-González  8
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Prevention of neutrophil extravasation by α2-adrenoceptor-mediated endothelial stabilization

Ada María Herrera-García et al. J Immunol. .

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.

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