During responses to infection and tissue injury, circulating leukocytes and platelets adhere to each other and to the endothelial surface of blood vessels. Dysregulated adhesion of these cells contributes to thrombotic and inflammatory disorders. Leukocytes first tether to and then roll on vascular surfaces, a prerequisite for the subsequent arrest and then migration of the cells into the underlying tissues.

Tethering and rolling require rapid interaction of three related cell adhesion molecules called selectins with glycosylated cell-surface ligands. These interactions must withstand the forces applied to adherent cells by the wall shear stresses in the circulation. We discovered a sialomucin called PSGL-1, which is the major ligand on leukocytes for P-selectin and L-selectin and which also binds to E-selectin.

We have identified a number of molecular and cellular features that govern how selectins bind to their glycoconjugate ligands. These include the extension of binding domains above the cell surface, the clustering of selectins or their ligands through interactions of the cytosolic domains with clathrin-coated pits or the cytoskeleton and the dynamic extension and retraction of long, thin membrane tethers during rolling adhesion. We discovered that different levels of force affect the lifetimes of selectin-ligand bonds in a biphasic manner. Low forces prolong lifetimes (catch bonds), whereas higher forces shorten lifetimes (slip bonds). Catch bonds help explain the paradoxical requirement for a minimum flow rate to support cell adhesion mediated through L-selectin.

Studies with gene-targeted mice have a identified a novel role for PSGL-1 in mediating tethering of flowing leukocytes to E-selectin on inflamed vascular surfaces, a function for core 1-derived O-glycans in angiogenesis during development, and an unexpected contribution of cytokine receptors in bone marrow endothelial cells for hematopoiesis.

We are using biochemical and crystallographic approaches to further refine the structural features involved in selectin-ligand interactions, flow chambers to study the biophysical features required for selectins to support cell interactions under flow and a variety of gene-targeted mice to study the functions of selectins, PSGL-1, glycosyltransferases and cytokine receptors in vivo. Our long-term goal is to understand how lectin-carbohydrate interactions in the vasculature contribute to inflammation, hemostasis and hematopoiesis.

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