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Dimerization of LFA‐1/ICAM‐1 bond provides a spatio‐temporal cue in PMN recruitment

Polymorphonuclear leukocyte (PMN) adhesion to the inflamed endothelium is in part mediated by LFA‐1 which recognizes its ligand ICAM‐1. It has long been known that ICAM‐1 rapidly forms homodimers and this conformation supports more stable bonds to high affinity LFA‐1 with lifetimes that are 10‐fold longer in duration and exhibit greater dynamic strength than monomeric ICAM‐1. We hypothesize that dimerization of the LFA‐1 bond to ICAM‐1 results in outside‐in signaling that serves as a gatekeeper in the transition from PMN arrest to a migratory phenotype. Imaging PMN rolling on an inflammatory mimetic substrate expressing E‐selectin and ICAM‐1 under shear flow revealed that calcium flux was markedly higher upon arrest on dimeric as compared to monomeric ICAM‐1. Immunofluorescence revealed colocalization of cytoplasmic F‐actin, Talin, Rap‐1, and phospho‐Src within regions correlating with high affinity clusters of LFA‐1. In summary, these data reveal that at a minimum, dimerization of LFA‐1/ICAM‐1 bonds elicits the assembly of a macromolecular complex that provides a key navigational step in the transition from PMN arrest to a migratory phenotype. This work was supported by AI47294 to S.I.S.