alpha(9)beta(1) integrin is expressed on human neutrophils and contributesto neutrophil migration through human lung and synovial fibroblast barriers

Accumulation of leukocytes in inflamed tissue involves their migration thro ugh vascular endothelium and then in the connective tissue, Recently we uti lized a barrier of human synovial, dermal, and lung fibroblasts (HSF, HDF, and HLF) grown on polycarbonate filters as a model of human polymorphonucle ar leukocyte (PMN) migration through connective tissue. The beta(2) integri ns (CD11/ CD18) and alpha(4), alpha(5), and alpha(6)beta(1) (VLA-4, -5, and -6) integrins each contributed to this PMN migration. Here we report that on human blood leukocytes, alpha(9)beta(1) (VLA-9) is expressed only on PMN s and that it is up-regulated after PMN activation, Based on monoclonal ant ibody (mAb) blocking studies, alpha(9)beta(1) integrin contributed to C5a-i nduced PMN migration through fibroblast (HLF and HSF) barriers, This role w as apparent only when alternate mechanisms such as CD18, alpha(4), alpha(5) , and alpha(6)beta(1) integrins were blocked and then mAb to alpha(9)beta(1 ) integrin inhibited the residual PMN migration (by 40-50%) through the HLF or HSF barrier, resulting in greater than or equal to 75% inhibition overa ll, In contrast, PMN migration across interleukin-1-activated endothelium ( HUVEC) in response to a C5a gradient, which is partly (30-40%) via CD11/CD1 8-independent mechanisms, was not inhibited by adhesion blocking by mAbs to alpha(4), alpha(5), alpha(6) and alpha(9)beta(1) even in combination, Thes e results indicate that alpha(9)beta(1) integrin on PMN may have a special role, in conjunction with other beta(1) integrins, in mediating PMN migrati on in the extravascular space, and may contribute to differential neutrophi l function within tissues.