Prevention of Neutrophil Extravasation by α2-Adrenoceptor–Mediated Endothelial Stabilization

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.

Brimonidine displays anti‐inflammatory properties in the skin through the modulation of the vascular barrier function

“…In addition, in an animal model of TPA‐induced acute inflammation and in an in vitro assay of acute vascular inflammation, brimonidine significantly reduced neutrophil recruitment. Furthermore, a decrease in neutrophil content in inflammatory foci in vivo with a systemic treatment with α2‐adrenergic agonists was previously observed, which is in line with the present results …”

“…In addition, α2A‐adrenergic receptors are also expressed in endothelial cells and human neutrophils. Moreover, α2‐agonists trigger signals that protect the integrity of endothelial adherent junctions during the inflammatory response . Moreover, we showed that endothelial cells are the main targets of α2A‐adrenergic agonists.…”

Integrative concepts of rosacea pathophysiology, clinical presentation and new therapeutics

“…Brimonidine acts by selectively binding to α2‐adrenergic receptors present on smooth muscle in the peripheral vasculature, resulting in transient local vasoconstriction and other vascular effects (Table ). Other α2 receptor agonists have further demonstrated the ability to reduce neutrophil extravasation and inhibit PGE2 release …”

The role of α2‐adrenergic receptors in hypertensive preeclampsia: A hypothesis

“…In the context of peripheral inflammation, while COX‐2 inhibition was shown to attenuate neutrophil‐endothelium interaction, a key step in inflammation‐evoked endothelial dysfunction in PE, a similar role for α 2 ‐AR modulation in this process cannot be discounted. Indeed, an anti‐inflammatory role for α 2 ‐AR agonists, evident by decreased endothelial‐leukocyte interaction, has been reported . α 2 ‐AR agonists caused an increase in the resistance of ECs to neutrophil extravasation, through inhibition of TNF‐α‐decreased expression of adhesion molecules .…”

“…Indeed, an anti‐inflammatory role for α 2 ‐AR agonists, evident by decreased endothelial‐leukocyte interaction, has been reported . α 2 ‐AR agonists caused an increase in the resistance of ECs to neutrophil extravasation, through inhibition of TNF‐α‐decreased expression of adhesion molecules . Of course, more studies are needed to investigate the anti‐inflammatory effect of α 2 ‐ARs in placental preeclamptic tissues and animal models.…”