ABSENCE OF TRAUMA-INDUCED LEUKOCYTE ROLLING IN MICE DEFICIENT IN BOTHP-SELECTIN AND INTERCELLULAR-ADHESION MOLECULE-1

Leukocyte recruitment during inflammation is achieved through a multis tep paradigm that includes margination, selectin-mediated rolling, bet a(2) integrin-mediated firm adhesion, emigration, and migration into t he site of inflammation. We have used the mouse cremaster muscle as a model of trauma- and cytokine-induced inflammation to study the possib le role of intercellular adhesion molecule (ICAM) 1 in leukocyte rolli ng using gene-targeted mice deficient in ICAM-1, P-selectin, and a com bination of P-selectin and ICAM-1. Rolling flux and average leukocyte rolling velocity in ICAM-1-deficient mice was not different from wild- type mice, but P-selectin/ICAM-1-deficient mice showed a total absence of rolling for at least 2 h after surgical trauma. Rolling in both wi ld-type and ICAM-1-deficient mice 60-120 min after trauma was signific antly inhibited by a P-selectin monoclonal antibody (mAb) (RB40.34). I n contrast, an mAb (KAT-1) blocking ICAM-1 binding to leukocyte functi on-associated antigen 1 did not block residual rolling in P-selectin-d eficient mice. TNF-alpha induced leukocyte rolling in P-selectin/ICAM- 1-deficient mice, but the rolling nux fraction was significantly lower than in TNF-alpha-treated ICAM-1-deficient mice. Leukocyte rolling in P-selectin/ICAM-1-deficient mice treated with TNF-alpha for 3 h was c ompletely blocked by an E-selectin mAb (9A9E3), and partially by an L- selectin mAb (MEL-14). This clearly demonstrates E-selectin-dependent rolling in vivo. Leukocyte rolling velocities were significantly reduc ed after TNF-alpha treatment and were similar in wild-type and gene-ta rgeted strains. We conclude that the residual trauma-induced leukocyte rolling seen in P-selectin-deficient mice is completely abolished by concomitant ICAM-1 deficiency. This severe defect in leukocyte rolling may explain the absence of leukocyte recruitment into the inflamed pe ritoneal cavity of P-selectin/ICAM-1-deficient mice at early time poin ts (less than or equal to 4 h).