Letter abstract
Nature Medicine 15, 300 - 305 (2009)
Published online: 22 February 2009 | doi:10.1038/nm.1921
Kindlin-3 is required for 
2 integrin–mediated leukocyte adhesion to endothelial cells
Markus Moser1, Martina Bauer1, Stephan Schmid2, Raphael Ruppert1, Sarah Schmidt1, Michael Sixt1, Hao-Ven Wang1, Markus Sperandio2 & Reinhard Fässler1
Integrin activation is essential for the function of all blood cells, including platelets and leukocytes1. The blood cell–specific FERM domain protein Kindlin-3 is required for the activation of the 
1 and 3 integrins on platelets2. Impaired activation of 1, 2 and 3 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 endothelia3. Here we show that Kindlin-3 also binds the 2 integrin cytoplasmic domain and is essential for neutrophil binding and spreading on 2 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 1, 2 and 3 integrin classes, and loss of Kindlin-3 function is sufficient to cause a LAD-III–like phenotype in mice.
- Department of Molecular Medicine, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
- Walter Brendel Center for Experimental Medicine, Ludwig-Maximilians-Universität, Marchioninistrasse 15, 81377 Munich, Germany.
Correspondence to: Reinhard Fässler1 e-mail: faessler@biochem.mpg.de
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