Neutrophil arrest by LFA-1 activation

Lymphocyte function-associated antigen-1 (LFA-1) is a heterodimeric integrin consisting of alpha(L) (gene name, Itgal) and beta(2) (gene name, Itgb2) subunits expressed in all leukocytes. LEA-1 is essential for neutrophil recruitment to inflamed tissue. Activation of LEA-1 by chemokines allows neutrophils and other leukocytes to undergo arrest, resulting in firm adhesion on endothelia expressing intercellular adhesion molecules (ICAMs). In mice, CXCR2 is the primary chemokine receptor involved in triggering neutrophil arrest, and it does so through inside-out activation of LEA-1. CXCR2 signaling induces changes in LEA-1 conformation that are coupled to affinity upregulation of the ligand-binding headpiece (extended with open I domain). Unlike naive lymphocytes, engagement of P-selectin glycoprotein ligand-1 (PSGL-1) on neutrophils stimulates a slow rolling behavior that is mediated by LEA-1 in a distinct activation state (extended with closed I domain). How inside-out signaling cascades regulate the structure and function of LEA-1 is being studied using flow chambers, intravital microscopy, and flow cytometry for ligand and reporter antibody binding. Here, we review how LEA-1 activation is regulated by cellular signaling and ligand binding. Two FERM domain-containing proteins, talin-1 and Kindlin-3, are critical integrin co-activators and have distinct roles in the induction of LEA-1 conformational rearrangements.This review integrates these new results into existing models of LEA-1 activation.