Antibodies to CD18 influence neutrophil migration through extracellular matrix

Mac-1 (CD11b/CD18) is known to be involved in neutrophil (PMN) adhesion to endothelial cells and extracellular matrix. Although antibodies to CD18 are being tested for therapy in humans, their role in PMN migration through th e extracellular matrix is unknown. We used direct visualization to quantify PMN motility through reconstituted, three-dimensional gels of collagen typ e I. Gels were prepared with different concentrations of collagen (ranging from 0.1 to 1.0 mg/mL) and PMN migration was examined in the presence and a bsence of antibodies to CD18 (anti-CD18), with and without stimulation by N -formyl peptides. In low-concentration gels (<0.6 mg/mL), anti-CD18 had a s ignificant influence on PMN migration, increasing motility in unstimulated PMN by 90% at 0.3 mg/mL collagen, and decreasing motility in N-formyl-methi onyl-leucyl-phenylalanine (fMLP)-stimulated by PMN by 70% at 0.4 mg/mL coll agen. But anti-CD18 had no effect on the rate of cell migration through hig h-concentration collagen gels (>0.6. mg/mL). PMN migration through collagen gels is CD18-dependent but only under conditions of high hydration, sugges ting that CD18-mediated effects (e.g., adhesion to gel fibers) are only imp ortant when the fiber density is relatively low. Anti-CD18 inhibited, but d id not eliminate the adhesion of fMLP-stimulated PMN to the surface of coll agen gels, suggesting that cells use multiple mechanisms for gaining tracti on within the gel. Because of the multiple modes of interaction between mot ile cells and the deformable fiber matrix. Blockade of one component, such as CD18, can enhance the rate of cell migration under one set of conditions , and inhibit under another.