α₉β₁ Integrin is expressed on human neutrophils and contributes to neutrophil migration through human lung and synovial fibroblast barriers

Accumulation of leukocytes in inflamed tissue involves their migration through vascular endothelium and then in the connective tissue. Recently we utilized a barrier of human synovial, dermal, and lung fibroblasts (HSF, HDF, and HLF) grown on polycarbonate filters as a model of human polymorphonuclear leukocyte (PMN) migration through connective tissue. The β₂ integrins (CD11/CD18) and α₄, α₅, and α₆β₁ (VLA-4, -5, and -6) integrins each contributed to this PMN migration. Here we report that on human blood leukocytes, α₉β₁ (VLA-9) is expressed only on PMNs and that it is up- regulated after PMN activation. Based on monoclonal antibody (mAb) blocking studies, α₉β₁ integrin contributed to C5a-induced PMN migration through fibroblast (HLF and HSF) barriers. This role was apparent only when alternate mechanisms such as CD18, α₄, α₅, and α₆β₁ integrins were blocked and then mAb to α₉β₁ integrin inhibited the residual PMN migration (by 40- 50%) through the HLF or HSF barrier, resulting in ≥75% inhibition overall. In contrast, PMN migration across interleukin-1-activated endothelium (HUVEC) in response to a C5a gradient, which is partly (30-40%) via CD11/CD18- independent mechanisms, was not inhibited by adhesion blocking by mAbs to α₄, α₅, α₆, and α₉β₁ even in combination. These results indicate that α₉β₁ integrin on PMN may have a special role, in conjunction with other β₁ integrins, in mediating PMN migration in the extravascular space, and may contribute to differential neutrophil function within tissues.