Kindlin-3 is required for β₂ integrin-mediated leukocyte adhesion to endothelial cells

Integrin activation is essential for the function of all blood cells, including platelets and leukocytes. The blood cell-specific FERM domain protein Kindlin-3 is required for the activation of the β₁ and β₃ integrins on platelets. Impaired activation of β₁, β₂ and β₃ integrins on platelets and leukocytes is the hallmark of a rare autosomal recessive leukocyte adhesion deficiency syndrome in humans called LAD-III, characterized by severe bleeding and impaired adhesion of leukocytes to inflamed endothelia. Here we show that Kindlin-3 also binds the β₂ integrin cytoplasmic domain and is essential for neutrophil binding and spreading on β₂ integrin-dependent ligands such as intercellular adhesion molecule-1 and the complement C3 activation product iC3b. Moreover, loss of Kindlin-3 expression abolished firm adhesion and arrest of neutrophils on activated endothelial cells in vitro and in vivo, whereas selectin-mediated rolling was unaffected. Thus, Kindlin-3 is essential to activate the β₁, β₂ and β₃ integrin classes, and loss of Kindlin-3 function is sufficient to cause a LAD-III-like phenotype in mice.