OPTIMAL SELECTIN-MEDIATED ROLLING OF LEUKOCYTES DURING INFLAMMATION IN-VIVO REQUIRES INTERCELLULAR-ADHESION MOLECULE-1 EXPRESSION

Leukocyte interactions with vascular endothelium during inflammation o ccur through discrete steps involving selectin-mediated leukocyte roll ing and subsequent firm adhesion mediated by members of the integrin a nd Ig families of adhesion molecules. To identify functional synergy b etween selectin and Ig family members, mice deficient in both L-select in and intercellular adhesion molecule 1 (ICAM-1) were generated. Leuk ocyte rolling velocities in cremaster muscle venules were increased si gnificantly in ICAM-1-deficient mice during both trauma- and tumor nec rosis factor alpha-induced inflammation, but rolling leukocyte flux wa s not reduced. Elimination of ICAM-1 expression in L-selectin-deficien t mice resulted in a sharp reduction in the flux of rolling leukocytes during tumor necrosis factor alpha-induced inflammation. The observed differences in leukocyte rolling behavior demonstrated that ICAM-1 ex pression was required for optimal P- and L-selectin-mediated rolling. Increased leukocyte rolling velocities presumably translated into decr eased tissue emigration because circulating neutrophil, monocyte, and lymphocyte numbers were increased markedly in L-selectin/ICAM-1-defici ent mice. Furthermore, neutrophil emigration during acute peritonitis was reduced by 80% in the double-deficient mice compared with either L -selectin or ICAM-1-deficient mice. Thus, members of the selectin and Ig families function synergistically to mediate optimal leukocyte roll ing in vivo, which is essential for the generation of effective inflam matory responses.