The oq-Integrin Supports Leukocyte Rolling and Adhesion in Chronically Inflamed PostcapillaryVenules In Vivo

A role for the 0~4-integrin (OL4~ 1 o r 0t.4~7) , has been imphcated in the recruitment of peripheral blood mononuclear cells (PBMCs) to sites of inflammation. However, the adhesive interactions (i.e., tethering, rolling, and adhesion) mediated by the ot4-integrin have not been characterized in vivo. The objective of this study was to establish a model wherein postcapillary venules were chronically inflamed, and then use intravital microscopy to identify the adhesive interactions mediated by the ot4-integrin in vivo. Between 4 and 20 d after immunization with Mycobacterium butyricum, animals developed a systemic vasculitis characterized by large increases in the numbers of rolling and adhering leukocytes within mesenteric venules. The selectins could only account for " 5 0 % of the leukocyte rolling whereas the remaining cells rolled exclusively via the ot4-integrin. Anti-or 4 therapy also ehminated the increase in leukocyte adhesion observed in this model, whereas selectin therapies and an anti-CD18 ([32-integrin) monoclonal antibody (mAb) did not reduce adhesion. A serum against polymorphonuclear leukocytes (PMNs) was used to confirm that a significant proportion of rolling cells, and most of the adhering cells were PBMCs. Sequential treatment with anti-PMN serum and the anti-cq mAb demonstrated that ot4-dependent rolling was distinct from PMN rolling populations. Initial leukocyte tethering via the ot4-integrin could not be demonstrated in this model, whereas L-selectin did support leukocyte tethering. These data suggest that the o~4-integrin can mediate both rolling and adhesion in the multistep recruitment of PMBCs in vivo, and these interactions occur independently of the selectins and [32-integrins.