Mice lacking two or all three selectins demonstrate overlapping and distinct functions for each selectin

Selectins support the capture and rolling of leukocytes in venules at sites of inflammation and in lymphocyte homing. Gene-targeted mice with null mut ations at the L-, E-, or P-selectin locus develop normally and show mild (E -/-) to moderate (P-/-, L-/-) defects in inflammatory cell recruitment. Mic e lacking both P- and E-selectin (E/P-/-) have severe neutrophilia and spon taneous skin infections that limit their life span. Other combinations of s electin deficiency have not been investigated. We have generated novel mice lacking L- and P-selectin (L/P-/-), L- and E-selectin (L/E-/-), or all thr ee selectins (E/L/P-/-) by bone marrow transplantation. L/P-/- mice (only E -selectin present) show an absence of leukocyte rolling after trauma and se verely reduced rolling (by similar to 90%) in inflammation induced by TNF-a lpha. Residual rolling in L/P-/- mice was very slow (3.6 +/- 0.2 mu m/s aft er TNF-alpha). L/E-/- mice (only P-selectin present) showed rolling similar to that of L-/- at increased velocities (15.1 +/- 0.3 mu m/s). The number of adherent leukocytes after 2 or 6 h of TNF-alpha treatment was not signif icantly reduced in L/E-/- or L/P-/- mice. E/L/P-/- mice showed very little rolling after TNF-alpha, all of which was blocked by mAb to alpha(4) integr in. Adherent and emigrated neutrophils were significantly reduced at 6 h af ter TNF-alpha. We conclude that any one of the selectins can support some n eutrophil recruitment but eliminating all three selectins significantly imp airs neutrophil recruitment.