Sialyltransferase ST3Gal-IV controls CXCR2-mediated firm leukocyte arrest during inflammation.
Recent in vitro studies have suggested a role for sialylation in chemokine receptor binding to its ligand (Bannert, N., S. Craig, M. Farzan, D. Sogah, N.V. Santo, H. Choe, and J. Sodroski. 2001. J. Exp. Med. 194:1661-1673). This prompted us to investigate chemokine-induced leukocyte adhesion in inflamed cremaster muscle venules of alpha2,3 sialyltransferase (ST3Gal-IV)-deficient mice. We found a marked reduction in leukocyte adhesion to inflamed microvessels upon injection of the CXCR2 ligands CXCL1 (keratinocyte-derived chemokine) or CXCL8 (interleukin 8). In addition, extravasation of ST3Gal-IV(-/-) neutrophils into thioglycollate-pretreated peritoneal cavities was significantly decreased. In vitro assays revealed that CXCL8 binding to isolated ST3Gal-IV(-/-) neutrophils was markedly impaired. Furthermore, CXCL1-mediated adhesion of ST3Gal-IV(-/-) leukocytes at physiological flow conditions, as well as transendothelial migration of ST3Gal-IV(-/-) leukocytes in response to CXCL1, was significantly reduced. In human neutrophils, enzymatic desialylation decreased binding of CXCR2 ligands to the neutrophil surface and diminished neutrophil degranulation in response to these chemokines. In addition, binding of alpha2,3-linked sialic acid-specific Maackia amurensis lectin II to purified CXCR2 from neuraminidase-treated CXCR2-transfected HEK293 cells was markedly impaired. Collectively, we provide substantial evidence that sialylation by ST3Gal-IV significantly contributes to CXCR2-mediated leukocyte adhesion during inflammation in vivo.
Children's Hospital, University of Heidelberg, 69120 Heidelberg, Germany.
David
D
Frommhold
Andreas
A
Ludwig
M Gabriele
MG
Bixel
Alexander
A
Zarbock
Inna
I
Babushkina
Melitta
M
Weissinger
Sandra
S
Cauwenberghs
Lesley G
LG
Ellies
Jamey D
JD
Marth
Annette G
AG
Beck-Sickinger
Michael
M
Sixt
Bärbel
B
Lange-Sperandio
Alma
A
Zernecke
Ernst
E
Brandt
Christian
C
Weber
Dietmar
D
Vestweber
Klaus
K
Ley
Markus
M
Sperandio
D000818:Animals; D002196:Capillaries / Q000502:physiology; D002448:Cell Adhesion; D004730:Endothelium, Vascular / Q000502:physiology / Q000503:physiopathology; D006439:Hemodynamics; D007249:Inflammation; D007962:Leukocytes / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology; D023063:Receptors, Interleukin-8B / Q000172:deficiency / Q000502:physiology*; D012016:Reference Values; D012799:Sialyltransferases / Q000378:metabolism*; D014699:Venules / Q000502:physiology / Q000503:physiopathology; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
D023063:Receptors, Interleukin-8B; D012799:Sialyltransferases; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase