Deficiency of the Sialyltransferase St3Gal4 Reduces-Ccl5Mediated Myeloid Cell Recruitment and Arrest

Yvonne Doering*, Heidi Noels, Manuela Mandl, Birgit Kramp, Carlos Neideck, Dirk Lievens, Maik Drechsler, Remco T. A. Megens, Pathricia V. Tilstam, Marcella Langer, Helene Hartwig, Wendy Theelen, Jamey D. Marth, Markus Sperandio, Oliver Soehnlein, Christian Weber

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Rationale: Sialylation by 2,3-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 2,3-sialyltransferase IV (ST3Gal-IV) in Ccl5- and Ccl2-mediated myeloid cell arrest and further studied its relevance in a mouse model of atherosclerosis. Methods and 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--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.
Original languageEnglish
Pages (from-to)976-981
JournalCirculation Research
Volume114
Issue number6
DOIs
Publication statusPublished - 14 Mar 2014

Keywords

  • atherosclerosis
  • beta-galactoside alpha-2
  • 3-sialyltransferase

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