The interplay between integrins α_Mβ₂ and α₅β₁ during cell migration to fibronectin

A directed migration of leukocytes through the extracellular matrix requires the regulated engagement of integrin cell adhesion receptors. The integrin α_Mβ₂ (CD11b/CD18, Mac-1) is progressively upregulated to high levels on migrating phagocytic leukocytes in response to inflammatory stimuli and is able to bind numerous ligands in the interstitial matrix. The role of α_Mβ₂ in migration of leukocytes through the extracellular matrix and its cooperation with other leukocyte integrins during migration are not understood. Using a model system consisting of cells that express different levels of α_Mβ₂ and an invariable level of endogenous integrin α₅β₁, we have explored a situation relevant to migrating neutrophils when α_Mβ₂ and α₅β₁ engage the same ligand, fibronectin. We show that fibronectin is a ligand for α_Mβ₂ and that both α_Mβ₂ and α₅β₁ on the α_Mβ₂-expressing cells contribute to adhesion to fibronectin. However, migration of these cells to fibronectin is mediated by α₅β₁, whereas α_Mβ₂ retards migration. The decrease in migration correlates directly with the increased α_Mβ₂ density. Ligation of α_Mβ₂ with function-blocking antibodies can reverse this effect. The restorative effects of antibodies are caused by the removal of restraint imposed by the excess of α_Mβ₂-fibronectin adhesive bonds. These findings indicate that α_Mβ₂ can increase general cell adhesiveness which results in braking of cell migration mediated by integrin α₅β₁. Because α_Mβ₂ binds numerous proteins in the extracellular matrix with a specificity overlapping that of the β₁ integrins, the results suggest that α_Mβ₂ can affect the β₁ integrin-mediated cell migration.