Molecular Mechanisms of Neutrophil Adhesion Studied by Inducing a High Avidity State at β2-Integrin

Abstract

The immune host response of neutrophils is dependent upon adhesion to endothelium, chemotaxis into the periferral tissue, and phagocytosis of microorganisms. Essential to these adhesion dependent functions are the Leu-CAM family of β2-integrin adhesive molecules which consist of 3 distinct alpha subunits (LFA-1 CD11a, Mac-1 CD11b, and P150.95 CD11c), noncovalently linked to a common beta subunit (CD18) (for review see ref. 1). The physiologic role of these adhesion molecules is elucidated in patients presenting with a deficiency in leukocyte integrins. These patients suffer from opportunistic infections due to an inability of their neutrophils to firmly adhere and migrate across the endothelium and fight tissue borne infections (2). Normal neutrophils isolated from blood respond to the binding of chemotactic formyl peptide to its surface receptor by an increase in the adhesive avidity of CD18 to bind a multitude of ligands including ICAM-1, fibrinogen, and an as yet uncharacterized ligand on the neutrophil plasma membrane (3). At saturating doses of chemotactic peptide (>500 nM) Mac-1 is rapidly mobilized to the plasma membrane from intracellular granular stores, increasing the surface expression ≈10 fold over constitutive levels (3). However, recent studies from our laboratory and others indicate that only a portion of these sites participate in adhesion. Stimulation of neutrophils in a step-wise fashion by binding nanomolar concentrations of formyl peptide results in newly mobilized Mac-1 which participate in adherence-dependent locomotion (4). It has been recently reported that as little as 10% of the surface Mac-1 on activated cells participate in binding to fibrinogen and ICAM-1 (5). The high avidity state of Mac-1 appears to be mediated by a change in the structure or conformation of the epitope.