CCR3-active chemokines influence eosinophil adhesion to endothelial cells under static and flow conditions

We recently demonstrated that CCR3-active chemokines promote rapid detachment of eosinophils bound to vascular cell adhesion molecule-1 (VCAM-1) in vitro. Eosinophils adhered well to immobilized human recombinant VCAM-1 primarily via α₄β₁ integrin. Eotaxin-2, a CCR3-specific chemokine, induced eosinophil de-adhesion from VCAM-1. In contrast, very few eosinophils spontaneously adhered to bovine serum albumin (BSA), and eosinophil adhesion to BSA was enhanced by eotaxin-2 over a similar nm range of concentrations. This enhancement of BSA adhesion was dependent on β₂ integrins. Eosinophil α₄β₁ integrins can mediate rolling on VCAM-1 under physiological flow conditions. Although we observed a reduction of eosinophil accumulation on immobilized VCAM-1 in response to eotaxin-2 under physiological flow conditions, this reduction of adhesion was not observed when VCAM-1 and intercellular adhesion molecule-1 (ICAM-1) were co-immobilized. Based on antibody-blocking studies, this appears to be caused by a chemokine-induced shift in integrin usage away from β₁ integrin-dominated interactions with VCAM-1 towards β₂ integrin-dominated interactions with ICAM-1. Our results confirm the important role of integrins and chemokines in selective eosinophil migration processes. CCR3-active chemokines may be necessary to facilitate de-adhesion from luminal VCAM-1 and to facilitate the process of diapedesis by shifting integrin usage in eosinophils away from β₁ integrin-dominated interactions with VCAM-1 towards β₂ integrin-dominated interactions with ICAM-1. The critical importance of integrins and chemokines in eosinophilic inflammation lends support for targeting these molecules with novel therapeutic agents.