Biomechanics of leukocyte rolling

Abstract

Leukocyte rolling on endothelial cells and other P-selectin substrates is mediated by P-selectin binding to P-selectin glycoprotein ligand-1 expressed on the tips of leukocyte microvilli. Leukocyte rolling is a result of rapid, yet balanced formation and dissociation of selectin-ligand bonds in the presence of hydrodynamic shear forces. The hydrodynamic forces acting on the bonds may either increase (catch bonds) or decrease (slip-bonds) their lifetimes. The force-dependent ‘catch-slip’ bond kinetics are explained using the ‘two pathway model’ for bond dissociation. Both the ‘sliding-rebinding’ and the ‘allosteric’ mechanisms attribute ‘catch-slip’ bond behavior to the force-induced conformational changes in the lectin-EGF domain hinge of selectins. Below a threshold shear stress, selectins cannot mediate rolling. This ‘shear-threshold’ phenomenon is a consequence of shear-enhanced tethering and catch-bond enhanced rolling. Quantitative dynamic footprinting microscopy has revealed that leukocytes rolling at venular shear stresses (> 0.6 Pa) undergo cellular deformation (large footprint) and form long tethers. The hydrodynamic shear force and torque acting on the rolling cell are thought to be synergistically balanced by the forces acting on tethers and stressed microvilli, however, their relative contribution remains to be determined. Thus, improvement beyond the current understanding requires in silico models that can predict both cellular and microvillus deformation and experiments that allow measurement of forces acting on individual microvilli and tethers.

Cancer and inflammation

“…Vascular dilation and hyperpermeability – the early events of inflammation – also enhance the transport of circulating immune cells to the tissue, and this aspect of inflammation has been reviewed extensively (17, 104). As the plasma is filtered across the vessel, the blood gets more concentrated, increasing hematocrit.…”

The Plasma Membrane Flattens Out to Fuel Cell-Surface Growth during Drosophila Cellularization

“…Microvilli are found on most cell types from polarized epithelia of kidney, liver and lung, to neurosensory cells, Schwann cells, immune cells, and embryos (Revenu et al, 2004). Accordingly, the functions attributed to microvilli are wide-ranging: Microvilli increase surface area to promote absorption of water in the kidney, exposure of digestive enzymes in the gut, and adhesion of lymphocytes to vessel walls (Ashworth and Molitoris, 1999; Louvard et al, 1992; Sundd et al, 2011). In highly specialized forms, microvillar protrusions, like stereocilia in the inner ear, mediate mechanotransduction (Hudspeth and Corey, 1977).…”

Neutrophil rolling at high shear: Flattening, catch bond behavior, tethers and slings

“…; Nobis et al, 1985; Schmid-Schonbein et al, 1980), where they adhere to the vascular endothelium via an adhesion cascade which consists of sequential but overlapping steps of capture and rolling, followed by slow rolling, activation, and firm arrest (Ley et al, 2007; Springer, 1994). The primary steps of capture and rolling are mediated by rapid but reversible bonds between the selectin family of adhesion molecules (P- and E-selectin) expressed on endothelial cells (ECs) or neutrophils (L-selectin) and their glycoprotein ligands expressed on leukocytes and ECs (McEver and Zhu, 2010; Sundd et al, 2011). Selectins are type I transmembrane glycoproteins with an N-terminal Ca 2+ -dependent-carbohydrate-recognizing lectin domain, followed by an epidermal growth factor (EGF) like domain, a series of short consensus repeats, a transmembrane domain, and a short cytoplasmic domain (Kansas, 1996; McEver, 2002; McEver et al, 1995; Springer, 1990; Tedder et al, 1995; Vestweber and Blanks, 1999).…”