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. [ABSTRACT FROM AUTHOR]