Nano-to-microscale mechanical switches and fuses mediate adhesive contacts between leukocytes and the endothelium

Volkmar Heinrich, Andrew Leung, and Evan Evans

Boston University, Dept. of BME, and University of British Columbia, Depts. of Pathology and Physics

Mimicking the brief attachments of leukocytes to vessel walls in blood flow, we have examined the dynamic response of adhesive linkages between white cells and immobilized P-selectin, as well as between P-selectin and its ligand PSGL-1, to an external pulling force. Using the biomembrane force probe (BFP) we identified several regulatory mechanisms for the lifetime of these contacts. On the nanoscale, the P-selectin:PSGL-1 complex was found to act as a mechano-chemical switch between two distinct, loading-rate-dependent unbinding pathways, strengthening attachments that are loaded fast. The average lifetime of cellular attachments is prolonged further by a “molecular fuse” mechanism, relieving bond stress through the extrusion of membrane tethers. We show that as a prerequisite for tether formation, the intracellular anchor of the transmembrane PSGL-1 has to be released, and that this process exhibits the characteristic signature of breaking a weak chemical bond. Moreover, the dependence of the tethering force on the extrusion speed is not linear, as reported earlier, but follows a weak power law that is due to the shear-thinning behavior of cell material as it flows onto the tether. Together, these mechanisms enable leukocytes to patrol vessel walls largely unaffected by variations in the bloodstream’s shear rate.

Email: volkmar@bu.edu

Address: Volkmar Heinrich, Boston University, BME, 44 Cummington Street, Boston, MA 02215, USA