α4 and β2 integrins have nonredundant roles for asthma development, but for optimal allergen sensitization only α4 is critical

Objective

Recruitment of effector cell subsets to inflammatory lung, together with airway resident cells responsive to secreted products, play pivotal roles in developing and maintaining asthma. Differential use of adhesion molecules dictates the recruitment patterns of specific cell subsets, yet a clear understanding of the distinctive adhesive molecular pathways guiding them to lung is lacking. To provide further insight into the role of α4β1/VCAM-1 pathway and to compare this to the role of β2 integrin in the development of acute asthma phenotype, we used genetically deficient mice, in contrast to previous studies with anti-functional antibodies yielding ambiguous results.

Methods

Allergen-dependent airway inflammation and hyperresponsiveness was induced in conditional α4^Δ/Δ, VCAM-1^−/−, and β2^−/− mice. Cytology, immunocytochemistry, cytokine and immunoglobulin measurements, and cell type accumulation in lung, BAL fluid, plasma, and hemopoietic tissues were carried out.

Results

Asthma phenotype was totally abrogated in α4- or β2-deficient mice. Adoptive transfer of sensitized α4^Δ/Δ CD4⁺ cells into challenged normal mice failed to induce asthma, whereas α4^+/+ CD4⁺ cells were able to induce asthma in challenged α4^Δ/Δ mice. Parallel studies with β2^−/− or VCAM-1^−/− mice uncovered novel mechanistic insights in primary sensitization and into redundant or unique functional roles of these adhesion pathways in allergic asthma.

Conclusions

The lack of α4 integrin not only impedes the migration of all white cell subsets to lung and airways, but also prevents upregulation of vascular cell adhesion molecule-1 (VCAM-1) in inflamed lung vasculature and, unlike β2, attenuates optimal sensitization and ovalbumin-specific IgE production in vivo. As VCAM-1 deficiency did not protect mice from asthma, interactions of α4β1⁺ or α4β7⁺ cells with other ligands are suggested.