TNF-α Potentiates C5a-Stimulated Eosinophil Adhesion to Human Bronchial Epithelial Cells: A Role for α5β1 Integrin

Abstract

Cooperative action of inflammatory mediators and adhesion molecules orchestrates eosinophil recruitment during allergic inflammation in the airways. This study investigated the mechanisms involved in increasing eosinophil adhesion to human bronchial epithelial cells (HBEC) following priming and activation of eosinophils with TNF-α and complement protein C5a, respectively. Under primed conditions, eosinophil adhesion increased 3-fold from basal (16%), and the effect was significantly greater (p < 0.05) than the increase following stimulation with C5a alone (2-fold). Eosinophil contact with HBEC was essential for priming. In contrast to C5a, adhesion of eotaxin-stimulated eosinophils to HBEC was not primed with TNF-α nor IL-5, a known eosinophil-priming agent. Priming caused activation of αMβ2 integrin; mAb against either the common β2 integrin subunit or its ICAM-1 ligand reduced the primed component of adhesion. Using mAbs against β1 or α5, but not α4 integrin subunit, together with anti-β2 integrin mAb, reduced stimulated adhesion to basal levels. Cross-linking α5β1 integrin increased αMβ2 integrin-dependent adhesion of eosinophils. There are no known adhesion molecule ligands of α5β1 integrin expressed on HBEC; however, fibronectin, the major matrix protein ligand for α5β1 integrin, was detected in association with HBEC monolayers. A mAb against fibronectin, in combination with anti-β2 integrin mAb, reduced adhesion to basal levels. In conclusion, α5β1 integrin may provide a contact-dependent costimulus for eosinophil priming that, together with TNF-α, potentiated C5a activation of αMβ2 integrin and increased eosinophil adhesion to ICAM-1. Fibronectin, associated with HBEC, may act as a ligand for α5β1 integrin. Dual regulation of eosinophil priming may prevent inappropriate activation of eosinophils in the circulation.

Pharmacological Targeting of Anaphylatoxin Receptors during the Effector Phase of Allergic Asthma Suppresses Airway Hyperresponsiveness and Airway Inflammation

“…In contrast, C3a and C5a are potent chemoattractants (32,39) and activators (40) of human eosinophils suggesting a direct effect of both AT to recruit eosinophils to the airways. In fact, C3a (41) and C5a increase eosinophil adhesion to cytokine-activated and resting bronchial epithelial cells (39,42). Of note, the reduction of eosinophils after ATs receptor blockade is not associated with decreased IL-5 levels.…”

The Role of Complement in Inflammatory Diseases From Behind the Scenes into the Spotlight

“…It has been postulated that C5a is involved in eosinophil adhesion to bronchial epithelial cells during allergic inflammation in the airways. 34 Another study has shown that C5a is an activator of integrin-dependent adhesion and transmigration of eosinophils and neutrophils. 35 These examples indicate that anaphylatoxins can play a role in the process of extravasation, directly influencing the expression of adhesion molecules on endothelial cells as well as leukocytes.…”

Induction of adhesion molecules upon the interaction between eosinophils and bronchial epithelial cells: Involvement of p38 MAPK and NF-κB

“…In fact, our previous and present results have indicated that the interaction of eosinophils and bronchial epithelial cells exhibits synergistic effect for the release of chemokines, IL-6 and GM-CSF [23,24]. Epithelial cells in patients with allergic asthma and rhinitis express elevated levels of VCAM-1 and ICAM-1 [27], and eosinophil contact with epithelial cells is essential for eosinophil priming [28]. Therefore, our present results have further elucidated that the adhesion molecule-mediated activation upon interaction of eosinophils and epithelial cells could be the underlying mechanism, at least partly, for the activation of epithelial cells to release chemokines and cytokines.…”