No endothelial L‐selectin ligand mediates leukocyte rolling in inflammation

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The multistep process of leukocyte recruitment guides leukocyte trafficking and immune function. The leukocyte cell adhesion molecule (CAM) L-selectin is a key molecule in this process. Its role in inflammation has largely been attributed to the presence of an endothelial L-selectin ligand expressed on inflamed endothelium. However, the identity of this ligand(s) has been elusive. Here, we used intravital microscopy to show that the reduction of leukocyte rolling in inflammation following blockage of L-selectin is entirely dependent on loss of L-selectin/PSGL-1-dependent leukocyte-mediated secondary capture. Secondary capture initiates rolling mainly on endothelial E-selectin and function-inhibition of L-selectin or E-selectin thus blocks rolling of largely the same pool of rolling leukocytes. All rolling along endothelium in venules following six distinct treatment regimens were abolished after simultaneous blockage of P-selectin, E-selectin and VCAM-1 and no L-selectin ligand activity on endothelium was detected. These data show that there is no ligand for L-selectin mediating rolling along endothelium in inflamed venules. These findings may conclude the search for L-selectin ligands capable of mediating leukocyte rolling in inflammation.