|Title||Deficiency of the sialyltransferase St3Gal4 reduces Ccl5-mediated myeloid cell recruitment and arrest: short communication.|
|Publication Type||Journal Article|
|Year of Publication||2014|
|Authors||Döring Y, Noels H, Mandl M, Kramp B, Neideck C, Lievens D, Drechsler M, Megens RTA, Tilstam PV, Langer M, Hartwig H, Theelen W, Marth JD, Sperandio M, Soehnlein O, Weber C|
|Date Published||2014 Mar 14|
|Keywords||Animals, Apolipoproteins E, Atherosclerosis, Chemokine CCL2, Chemokine CCL5, Dietary Fats, Female, Inflammation, Intercellular Adhesion Molecule-1, Leukocyte Rolling, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Cells, N-Acetylneuraminic Acid, Neuraminidase, Protein Processing, Post-Translational, Sialyltransferases, Tumor Necrosis Factor-alpha, Vascular Cell Adhesion Molecule-1|
RATIONALE: 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.
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-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.
|Alternate Journal||Circ. Res.|
|Grant List||R01 GM100192 / GM / NIGMS NIH HHS / United States|