Airway recruitment of leukocytes in mice is dependent on alpha4-integrins and vascular cell adhesion molecule-1

Abstract

The involvement of the alpha4-integrin very late activation antigen 4 and vascular cell adhesion molecule-1 (VCAM-1) in leukocyte trafficking into the airways of ovalbumin (OA)-sensitized and OA-challenged mice was investigated using in vivo administration of anti-alpha4 monoclonal antibodies (mAb) PS/2, R1-2, and M/K-2.7 (MK2), specific for VCAM-1. VCAM-1 was upregulated on endothelial cells in lung tissue after OA inhalation. PS/2, R1-2, or MK2 significantly inhibited the recruitment of eosinophils and lymphocytes into the bronchoalveolar lavage (BAL) fluid and decreased inflammation in the lung tissues. Escalating in vivo doses of PS/2 or MK2 increased circulating levels of rat immunoglobulin G in the plasma. The binding of phycoerytherin-labeled anti-alpha4 mAb to blood T cells from PS/2-treated mice was reduced, implying that alpha4 sites were already occupied. T cells and eosinophils in BAL fluid from mice treated with PS/2 or MK2 were phenotypically different from controls. Selective decreases of alpha4+ T cells in the BAL fluid after PS/2 or MK2 treatment were coupled with changes in CD8+, CD11a, and CD62L expression. The alpha4-integrin and VCAM-1 may have important roles in the antigen-induced recruitment of T cells and eosinophils during OA-induced airway inflammation. The data suggest that these adhesion molecules may be suitable targets for therapeutic intervention in certain conditions of pulmonary inflammation.

Endothelial cell PTP1B regulates leukocyte recruitment during allergic inflammation

“…Thus there was binding of eosinophils to the endothelium but reduced transendothelial recruitment of the eosinophils into the tissue. These data are consistent with our previous reports that in vitro, endothelial cell PTP1B is a mediator of VCAM-1 signaling (16) and reports that VCAM-1 is required for infiltration of eosinophils in response to OVA challenge to the lung (12). This is also consistent with our previous report in which chimeric mice with a deficiency in nonhematopoietic NADPH oxidase 2 (NOX2), a VCAM-1 signal upstream of PTP1B, had accumulation of eosinophils on the endothelium and reduced eosinophils in the lung without altering lung adhesion molecules, cytokines, or chemokines (4).…”

“…In the present study with PTP1B deficiency in endothelial cells in vivo, there was a decrease in eosinophils, lymphocytes, and monocytes/macrophages, but not neutrophils, in OVA-challenged lungs of iePTP1B/Ϫdox mice. In the OVA model of allergic inflammation, eosinophils migrate on VCAM-1 (12), lymphocytes migrate on intercellular adhesion molecule 1 (ICAM-1), and partially migrate on VCAM-1 (12,30,33), and monocytes can migrate on VCAM-1 and ICAM-1 (35). In contrast, neutrophils primarily migrate on platelet endothelial cell adhesion molecule (PECAM-1) (13).…”

“…Thus vascular PTP1B may be a novel endothelial target for drug intervention in the limitation of the VCAM-1-dependent component of inflammations that have been implicated in diseases such as asthma (11,12), atherosclerosis (20,43), and multiple sclerosis (21). Moreover, limiting VCAM-1-dependent inflammation in chronic disease may be an advantageous target, since it would spare PECAM-1-independent inflammation such as neutrophil clearance of infections.…”

“…The mechanisms underlying eosinophil recruitment to the lung following allergen exposure are complex, involving the coordinate actions of adhesion molecules, the chemokine eotaxin, and T-cell-derived cytokines such as IL-5 (38,54). In particular, it has been shown that eosinophil recruitment to the lung in murine models of allergic inflammation is dependent upon eosinophil binding to the adhesion molecule vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells (12,26,44). Leukocyte binding to endothelial cell adhesion molecules including VCAM-1 (CD106) triggers active endothelial cell "outside-in" signals that regulate leukocyte migration in vitro (1,3,34,40,48,51).…”

P2Y2 Receptor Regulates VCAM-1 Membrane and Soluble Forms and Eosinophil Accumulation during Lung Inflammation

“…Infiltration of the airways by eosinophils seems to be central in the pathogenesis of asthma (3)(4)(5)(6). It involves the expression of adhesion molecules on the inflamed vascular endothelium.…”