Endothelial heparan sulfate deficiency impairs L-selectin- and chemokine-mediated neutrophil trafficking during inflammatory responses.
Here we have studied the involvement of endothelial heparan sulfate in inflammation by inactivating the enzyme N-acetyl glucosamine N-deacetylase-N-sulfotransferase-1 in endothelial cells and leukocytes, which is required for the addition of sulfate to the heparin sulfate chains. Mutant mice developed normally but showed impaired neutrophil infiltration in various inflammation models. These effects were due to changes in heparan sulfate specifically in endothelial cells. Decreased neutrophil infiltration was partially due to altered rolling velocity correlated with weaker binding of L-selectin to endothelial cells. Chemokine transcytosis across endothelial cells and presentation on the cell surface were also reduced, resulting in decreased neutrophil firm adhesion and migration. Thus, endothelial heparan sulfate has three functions in inflammation: by acting as a ligand for L-selectin during neutrophil rolling; in chemokine transcytosis; and by binding and presenting chemokines at the lumenal surface of the endothelium.
Wang
Lianchun
L
Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California 92093-0687, USA.
Fuster
Mark
M
Sriramarao
P
P
Esko
Jeffrey D
JD
D000581:Amidohydrolases / Q000172:deficiency; D000818:Animals; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines / Q000378:metabolism; D019743:Chemokines, CXC; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism; D006497:Heparan Sulfate / Q000737:chemistry / Q000172:deficiency* / Q000276:immunology; D007249:Inflammation / Q000276:immunology*; D019041:L-Selectin / Q000737:chemistry / Q000378:metabolism*; D036904:Leukocyte Rolling / Q000276:immunology; D008168:Lung / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism; D015238:Sulfotransferases / Q000172:deficiency
D000581:Amidohydrolases; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; D016207:Cytokines; D006497:Heparan Sulfate; D019041:L-Selectin; D019007:P-Selectin; D015238:Sulfotransferases; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; C074302:keratinocyte-derived chemokines; C491855:Ndst2 protein, mouse; C021350:heparitin sulfotransferase