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Selectin catch-slip kinetics encode shear threshold adhesive behavior of rolling leukocytes.

ABSTRACT: The selectin family of leukocyte adhesion receptors is principally recognized for mediating transient rolling interactions during the inflammatory response. Recent studies using ultrasensitive force probes to characterize the force-lifetime relationship between P- and L-selectin and their endogenous ligands have underscored the ability of increasing levels of force to initially extend the lifetime of these complexes before disrupting bond integrity. This so-called "catch-slip" transition has provided an appealing explanation for shear threshold phenomena in which increasing levels of shear stress stabilize leukocyte rolling under flow. We recently incorporated catch-slip kinetics into a mechanical model for cell adhesion and corroborated this hypothesis for neutrophils adhering via L-selectin. Here, using adhesive dynamics simulations, we demonstrate that biomembrane force probe measurements of various P- and L-selectin catch bonds faithfully predict differences in cell adhesion patterns that have been described extensively in vitro. Using phenomenological parameters to characterize the dominant features of molecular force spectra, we construct a generalized phase map that reveals that robust shear-threshold behavior is possible only when an applied force very efficiently stabilizes the bound receptor complex. This criteria explains why only a subset of selectin catch bonds exhibit a shear threshold and leads to a quantitative relationship that may be used to predict the magnitude of the shear threshold for families of catch-slip bonds directly from their force spectra. Collectively, our results extend the conceptual framework of adhesive dynamics as a means to translate complex single-molecule biophysics to macroscopic cell behavior.

SUBMITTER: Beste MT

PROVIDER: S-EPMC2634935 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Selectin catch-slip kinetics encode shear threshold adhesive behavior of rolling leukocytes.

Beste Michael T MT Hammer Daniel A DA

Proceedings of the National Academy of Sciences of the United States of America 20081218 52

The selectin family of leukocyte adhesion receptors is principally recognized for mediating transient rolling interactions during the inflammatory response. Recent studies using ultrasensitive force probes to characterize the force-lifetime relationship between P- and L-selectin and their endogenous ligands have underscored the ability of increasing levels of force to initially extend the lifetime of these complexes before disrupting bond integrity. This so-called "catch-slip" transition has pro ...[more]

PMID: 19095798

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Project description:Western blotting has proven to be an important technique in analysis of receptor-ligand interactions (i.e., by ligand blotting) and for identifying molecules mediating cell attachment (i.e., by cell blotting). Conventional ligand blotting and cell blotting methods employ nondynamic (static) incubation conditions, whereby molecules or cells of interest are placed in suspension and overlaid on membranes. However, many cell-cell and cell-matrix adhesive interactions occur under fluid shear conditions, and shear stress itself mediates and/or facilitates the engagement of these physiologically appropriate receptors and ligands. Notably, shear forces critically influence the adhesion of circulating cells and platelets to vessel walls in physiologic cell migration and hemostasis, as well as in inflammatory and thrombotic disorders, cancer metastasis, and atherosclerosis. Use of nondynamic blotting conditions to analyze such interactions can introduce bias, overtly missing relevant effectors and/or exaggerating the relative role(s) of nonphysiologic adhesion molecules. To address this shortfall, we have developed a new technique for identifying binding interactions under fluid shear conditions, the "blot rolling assay." Using this method, molecules in a complex mixture are resolved by gel electrophoresis, transferred to a membrane that is rendered semi-transparent, and the membrane is then incorporated into a parallel-plate flow chamber apparatus. Under controlled flow conditions, cells or particles bearing adhesion proteins of interest are then introduced into the chamber and interactions with individual immobilized molecules (bands) can be visualized in real-time. The substrate molecule(s) supporting adhesion under fluid shear can then be identified by staining with specific antibodies or by excising the relevant band(s) and performing mass spectrometry or microsequencing of the isolated material. This method thus allows for the identification, within a complex mixture and without prior isolation or purification, of both known and previously uncharacterized adhesion molecules operational under dynamic conditions.

Dataset Information

Selectin catch-slip kinetics encode shear threshold adhesive behavior of rolling leukocytes.

Publications

Selectin catch-slip kinetics encode shear threshold adhesive behavior of rolling leukocytes.

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