title: Deficiency of the sialyltransferase St3Gal4 reduces Ccl5-mediated myeloid cell recruitment and arrest: short communication.
abstract: BACKGROUND
  Sialylation by α2,3-sialyltransferases has been shown to be a crucial glycosylation step in the generation of functional selectin ligands. Recent evidence suggests that sialylation also affects the binding of chemokines to their corresponding receptor.
  
  
  OBJECTIVE
  Because the chemokine receptors for Ccl5 and Ccl2 are important in atherogenic recruitment of neutrophils and monocytes, we here investigated the role of α2,3-sialyltransferase IV (ST3Gal-IV) in Ccl5- and Ccl2-mediated myeloid cell arrest and further studied its relevance in a mouse model of atherosclerosis.
  
  
  RESULTS
  St3Gal4-deficient myeloid cells showed a reduced binding of Ccl5 and an impaired Ccl5-triggered integrin activation. Correspondingly, Ccl5-induced arrest on tumor necrosis factor-α-stimulated endothelium was almost completely abrogated, as observed in flow chamber adhesion assays and during ex vivo perfusion or intravital microscopy of carotid arteries. Moreover, Ccl5-triggered neutrophil and monocyte extravasation into the peritoneal cavity was severely reduced in St3Gal4(-/-) mice. In contrast, St3Gal4 deficiency did not significantly affect Ccl2 binding and only marginally decreased Ccl2-induced flow arrest of myeloid cells. In agreement with the crucial role of leukocyte accumulation in atherogenesis, and the importance of Ccl5 chemokine receptors mediating myeloid cell recruitment to atherosclerotic vessels, St3Gal4 deficiency drastically reduced the size, stage, and inflammatory cell content of atherosclerotic lesions in Apoe(-/-) mice on high-fat diet.
  
  
  CONCLUSIONS
  In summary, these findings identify ST3Gal-IV as a promising target to reduce inflammatory leukocyte recruitment and arrest.
authors.affiliation: From Institute for Cardiovascular Prevention (Y.D., M.M., B.K., C.N., D.L., M.D., R.T.A.M., M.L., H.H., O.S., C.W.), and Walter Brendel Centre of Experimental Medicine (M.S.), Ludwig-Maximilians University, Munich, Germany; Institute for Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany (H.N., P.V.T., W.T.); Center for Nanomedicine, Sanford-Burnham Medical Research Institute, University of California, Santa Barbara, CA (J.D.M.); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (M.S., O.S., C.W.); Academic Medical Center, Amsterdam, the Netherlands (O.S.); and Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands (R.T.A.M., C.W.).
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Döring
authors.forename: Heidi
authors.initials: H
authors.lastname: Noels
authors.forename: Manuela
authors.initials: M
authors.lastname: Mandl
authors.forename: Birgit
authors.initials: B
authors.lastname: Kramp
authors.forename: Carlos
authors.initials: C
authors.lastname: Neideck
authors.forename: Dirk
authors.initials: D
authors.lastname: Lievens
authors.forename: Maik
authors.initials: M
authors.lastname: Drechsler
authors.forename: Remco T A
authors.initials: RT
authors.lastname: Megens
authors.forename: Pathricia V
authors.initials: PV
authors.lastname: Tilstam
authors.forename: Marcella
authors.initials: M
authors.lastname: Langer
authors.forename: Helene
authors.initials: H
authors.lastname: Hartwig
authors.forename: Wendy
authors.initials: W
authors.lastname: Theelen
authors.forename: Jamey D
authors.initials: JD
authors.lastname: Marth
authors.forename: Markus
authors.initials: M
authors.lastname: Sperandio
authors.forename: Oliver
authors.initials: O
authors.lastname: Soehnlein
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D018932:Chemokine CCL2 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000502:physiology*; D004041:Dietary Fats / Q000633:toxicity; D005260:Female; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D036904:Leukocyte Rolling / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000473:pathology*; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D009439:Neuraminidase / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D012799:Sialyltransferases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
chemical_list: D001057:Apolipoproteins E; C491768:Ccl2 protein, mouse; C503460:Ccl5 protein, mouse; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D004041:Dietary Fats; C090509:Icam1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D012799:Sialyltransferases; D009439:Neuraminidase; D019158:N-Acetylneuraminic Acid; D000094663:beta-Galactoside alpha-2,3-Sialyltransferase
keywords: atherosclerosis; beta-galactoside alpha-2,3-sialyltransferase