The alpha 4-integrin supports leukocyte rolling and adhesion in chronically inflamed postcapillary venules in vivo.

Abstract

SummaryA role for the 0~4-integrin (OL4~ 1 or 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 "50% 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. There is a wealth of information describing the recruitment of PMNs from the mainstream of blood to sites ofextravascular injury. This multistep process is initiated by the tethering of PMNs to the endothehum, followed by weak transient adhesive interactions manifested as leukocyte rolling, leading ultimately to firm adhesion of PMNs to the vessel wall (1-4). If an appropriate chemotactic stimulus is present, firm adhesion then allows leukocytes to transmigrate across the vessel wall to sites of potential injury (5, 6). Different mechanisms appear to mediate PMN rolling and adhesion; rolling is dependent on selectins expressed on endothehum (P-selectin, E-selectin) and leukocytes (L-selectin), whereas firm adhesion is dependent on the binding of leukocyte integrins (CDll/CD18) to their ligands (intercellular adhesion molecule 1 [ICAM-1], etc.) found on endothehal cells (3,4,7,8). Intravital microscopy has played a critical role in establishing the molecular mechanisms underlying PMN rolling and adhesion as it provides a window for the direct observation of PMN behavior within intact postcapillary venules. However, because of a lack of chronic inflammatory models amenable to intravital microscopy, there is very htde information regarding the adhesive mechanisms that regulate the influx of other leukocytes su...

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