Agonist leukadherin-1 increases CD11b/CD18-dependent adhesion via membrane tethers

Biophys J. 2013 Dec 3;105(11):2517-27. doi: 10.1016/j.bpj.2013.10.020.


Integrin CD11b/CD18 is a key adhesion receptor that mediates leukocyte migration and immune functions. Leukadherin-1 (LA1) is a small molecule agonist that enhances CD11b/CD18-dependent cell adhesion to its ligand ICAM-1. Here, we used single-molecule force spectroscopy to investigate the biophysical mechanism by which LA1-activated CD11b/CD18 mediates leukocyte adhesion. Between the two distinct populations of CD11b/CD18:ICAM-1 complex that participate in cell adhesion, the cytoskeleton(CSK)-anchored elastic elements and the membrane tethers, we found that LA1 enhanced binding of CD11b/CD18 on K562 cells to ICAM-1 via the formation of long membrane tethers, whereas Mn(2+) additionally increased ICAM-1 binding via CSK-anchored bonds. LA1 activated wild-type and LFA1(-/-) neutrophils also showed longer detachment distances and time from ICAM-1-coated atomic force microscopy tips, but significantly lower detachment force, as compared to the Mn(2+)-activated cells, confirming that LA1 primarily increased membrane-tether bonds to enhance CD11b/CD18:ICAM-1 binding, whereas Mn(2+) induced additional CSK-anchored bond formation. The results suggest that the two types of agonists differentially activate integrins and couple them to the cellular machinery, providing what we feel are new insights into signal mechanotransduction by such agents.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Actin Cytoskeleton / metabolism
  • Amino Acid Sequence
  • Animals
  • Benzoates / chemistry
  • Benzoates / pharmacology*
  • Cell Adhesion
  • Cell Line, Tumor
  • Cell Membrane / chemistry
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism*
  • Humans
  • Intercellular Adhesion Molecule-1 / chemistry
  • Intercellular Adhesion Molecule-1 / metabolism*
  • Leukocytes / metabolism
  • Lymphocyte Function-Associated Antigen-1 / metabolism
  • Macrophage-1 Antigen / chemistry
  • Macrophage-1 Antigen / metabolism*
  • Manganese / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Molecular Docking Simulation
  • Molecular Sequence Data
  • Neutrophils / metabolism
  • Protein Binding
  • Thiohydantoins / chemistry
  • Thiohydantoins / pharmacology*


  • Benzoates
  • Lymphocyte Function-Associated Antigen-1
  • Macrophage-1 Antigen
  • Thiohydantoins
  • leukadherin-1
  • Intercellular Adhesion Molecule-1
  • Manganese