Two by two: The pairings of P-selectin and P-selectin glycoprotein ligand 1

Targeting of circulating leukocytes to specific areas of microbial invasion or tissue injury is critical for host defense and wound repair. If it is defective, syndromes of cellular immune deficiency result; conversely, if targeting is uncontrolled or dysregulated, accumulation of leukocytes may cause inflammatory tissue damage (1–3). In this issue of PNAS, Ramachandran and coworkers (4) report new aspects of the structure-function relationships of two molecules that are critical for precise targeting of myeloid leukocytes and certain other leukocyte subclasses: P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1). P-selectin is a member of the selectin family of adhesion molecules. PSGL-1 on the plasma membranes of neutrophils or monocytes, which are key effector cells of the innate immune system, binds to P-selectin translocated to the surfaces of inflamed endothelial cells or activated platelets (Fig. 1). Forces generated by flowing blood then cause the leukocytes to roll on the surfaces of the endothelial cells or adherent platelets (5, 6). The rolling interaction of myeloid leukocytes on stimulated endothelial cells is the initial cell–cell interaction in the acute inflammatory response. Engagement of PSGL-1 by P-selectin is particularly important at early time points (7, 8), although the rolling component of the multistep process of leukocyte targeting and transmigration to extravascular sites also can be accomplished by other adhesion molecules (5–9). Cell–cell interactions mediated by P-selectin and PSGL-1. Binding of P-selectin to PSGL-1 mediates rolling of leukocytes on inflamed endothelial cells (A) or adherent, activated platelets (B). (Neutrophils, or PMNs, are shown but other leukocyte subclasses also roll on P-selectin.) Engagement of PSGL-1 by P-selectin also mediates adhesion of platelets to …