Modulation of β1-integrins on hemopoietic progenitor cells after allergen challenge in asthmatic subjects

Background

Mobilization of hemopoietic progenitor cells from the bone marrow (BM) is a feature of inflammatory asthmatic responses. Understanding the mechanisms regulating progenitor cell mobilization and trafficking to the peripheral circulation might be important for the development of effective asthma therapies.

Objective

We investigated the role of adhesion molecules in the mobilization of hemopoietic progenitor cells from the BM during an allergen-induced asthmatic response.

Methods

BM and peripheral blood samples were obtained from dual-responders with mild asthma before and at several time points after allergen challenge. Fluctuations in expression and adhesive properties of β1- and β2-integrins on CD34⁺CD45⁺ progenitor cells were assessed by using flow cytometry and adhesion to protein-coated wells, respectively.

Results

On BM-derived CD34⁺CD45⁺ cells, expression of very late antigen (VLA) 4, but not VLA-5 or Mac-1, decreased significantly 24 hours after allergen challenge and had begun to recover by 48 hours after challenge. In peripheral blood allergen challenge induced a significant decrease in VLA-4 levels after 6 hours, which had not recovered by 96 hours after challenge. Similarly, VLA-5 expression decreased, most prominently at 72 to 96 hours after allergen challenge. In contrast, Mac-1 levels did not change. Chemokine-stimulated adhesion of BM-derived CD34⁺CD45⁺ cells to fibronectin was significantly attenuated 24 hours after challenge. Furthermore, adhesion to fibronectin and vascular cell adhesion molecule 1 was greatly reduced by anti-VLA-4 or anti-VLA-5 antibodies.

Conclusions

Preferential downregulation of β1-integrin expression on progenitor cells can reduce the tethering forces to BM components, thus facilitating their egress to the peripheral circulation during an allergic inflammatory response.

Key words: Adhesion, integrins, fibronectin, vascular cell adhesion molecule 1, egress, mobilization, asthma, allergen, inflammation

Abbreviations used: BM, Bone marrow, LFA, Leukocyte function–associated antigen, PB, peripheral blood, SDF, Stromal cell–derived factor, SMFI, Specific mean fluorescence intensity, VCAM, Vascular cell adhesion molecule, VLA, Very late antigen