Mice Lacking Two or All Three Selectins Demonstrate Overlapping and Distinct Functions for Each Selectin

Abstract

Selectins support the capture and rolling of leukocytes in venules at sites of inflammation and in lymphocyte homing. Gene-targeted mice with null mutations at the L-, E-, or P-selectin locus develop normally and show mild (E−/−) to moderate (P−/−, L−/−) defects in inflammatory cell recruitment. Mice lacking both P- and E-selectin (E/P−/−) have severe neutrophilia and spontaneous skin infections that limit their life span. Other combinations of selectin 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 three selectins (E/L/P−/−) by bone marrow transplantation. L/P−/− mice (only E-selectin present) show an absence of leukocyte rolling after trauma and severely reduced rolling (by ∼90%) in inflammation induced by TNF-α. Residual rolling in L/P−/− mice was very slow (3.6 ± 0.2 μm/s after TNF-α). L/E−/− mice (only P-selectin present) showed rolling similar to that of L−/− at increased velocities (15.1 ± 0.3 μm/s). The number of adherent leukocytes after 2 or 6 h of TNF-α treatment was not significantly reduced in L/E−/− or L/P−/− mice. E/L/P−/− mice showed very little rolling after TNF-α, all of which was blocked by mAb to α4 integrin. Adherent and emigrated neutrophils were significantly reduced at 6 h after TNF-α. We conclude that any one of the selectins can support some neutrophil recruitment but eliminating all three selectins significantly impairs neutrophil recruitment.