Leukocyte entry into sites of inflammation requires overlapping interactions between the L-selectin and ICAM-1 pathways

Leukocyte interactions with vascular endothelium during inflammation depend on cascades of adhesion molecule engagement, particularly during selectin- mediated leukocyte rolling. Leukocyte rolling is also facilitated by member s of the integrin and Ig families. Specifically, leukocyte rolling velociti es during inflammation are significantly increased in ICAM-1-deficient mice , with ICAM-1 expression required for optimal P- and L-selectin-mediated ro lling. Elimination of ICAM-1 expression in L-selectin-deficient mice signif icantly reduces leukocyte rolling. Whether disrupted leukocyte rolling in L -selectin and ICAM-1 double-deficient (L-selectin/ICAM-1(-/-)) mice affects leukocyte entry into sites of inflammation in vivo was assessed in the cur rent study by using experimental models of inflammation; thioglycollate-ind uced peritonitis, chemokine-induced neutrophil migration to the skin, delay ed-type hypersensitivity responses, rejection of allogeneic skin grafts, an d septic shock. In many cases, the loss of both L-selectin and ICAM-1 expre ssion dramatically reduced leukocyte migration into sites of inflammation b eyond what was observed with loss of either receptor alone. In fact, the ef fects from loss of both L-selectin and ICAM-1 effectively eliminated multip le chronic inflammatory responses in L-selectin/ICAM-1(-/-) mice. By contra st, the combined loss of L-selectin and ICAM-1 expression had minimal effec ts on the generation of Ag-specific T cell responses or humoral immunity. T hus, members of the selectin and Ig families function synergistically to me diate optimal leukocyte rolling and entry into tissues, which is essential for the generation of effective inflammatory responses in vivo.