Kindlin-3 is required for beta2 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 beta1 and beta3 integrins on platelets. Impaired activation of beta1, beta2 and beta3 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 beta2 integrin cytoplasmic domain and is essential for neutrophil binding and spreading on beta2 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 beta1, beta2 and beta3 integrin classes, and loss of Kindlin-3 function is sufficient to cause a LAD-III-like phenotype in mice.
Moser
Markus
M
Department of Molecular Medicine, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
Bauer
Martina
M
Schmid
Stephan
S
Ruppert
Raphael
R
Schmidt
Sarah
S
Sixt
Michael
M
Wang
Hao-Ven
HV
Sperandio
Markus
M
Fässler
Reinhard
R
D000818:Animals; D018821:CD18 Antigens / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology*; D006801:Humans; D007962:Leukocytes / Q000166:cytology*; D008024:Ligands; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000502:physiology*
D018821:CD18 Antigens; C477322:FERMT3 protein, human; D008024:Ligands; D008565:Membrane Proteins; D009363:Neoplasm Proteins