Severe impairment of leukocyte recruitment in ppGalNAcT-1-deficient mice

• Published in: The Journal of immunology (1950) 2012-06, Vol.188 (11), p.5674-5681
• Main Authors: Block, Helena, Ley, Klaus, Zarbock, Alexander
• Format: Article
• Language: English
• Subjects: Animals; Carbohydrate Conformation; Cell Movement - genetics; Cell Movement - immunology; Inflammation - enzymology; Inflammation - genetics; Inflammation - immunology; Leukocyte Rolling - genetics; Leukocyte Rolling - immunology; Ligands; Membrane Glycoproteins - metabolism; Mice; Mice, Knockout; N-Acetylgalactosaminyltransferases - deficiency; N-Acetylgalactosaminyltransferases - genetics; N-Acetylgalactosaminyltransferases - metabolism; P-Selectin - metabolism; Polypeptide N-acetylgalactosaminyltransferase; Polysaccharides - metabolism; Radiation Chimera; Severity of Illness Index
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1200392

P-selectin glycoprotein ligand-1 plays an important role in leukocyte recruitment. Its binding affinity to selectins is modulated by posttranslational modifications. The polypeptide N-acetylgalactosamine transferase-1 (ppGalNAcT-1) initiates core-type protein O-glycosylation. To address whether the glycosylation of P-selectin glycoprotein ligand-1 by ppGalNAcT-1 is important for leukocyte recruitment in vivo, we investigated leukocyte recruitment in untreated and TNF-α-treated cremaster muscles comparing ppGalNAcT-1-deficient mice (Galnt1(-/-)) and wild-type mice. In untreated and TNF-α-treated Galnt1(-/-) mice, leukocyte rolling, adhesion, and transmigration were significantly reduced, with markedly increased rolling velocity compared with control mice. L-selectin-dependent leukocyte rolling was completely abolished in Galnt1(-/-) mice compared with wild-type mice. Thioglycollate-induced peritonitis experiments with chimeric mice revealed that hematopoietic ppGalNAcT-1 is important for leukocyte recruitment. These data show that the loss of ppGalNAcT-1 led to reduced leukocyte rolling and recruitment and increased rolling velocity, suggesting a predominant role for ppGalNAcT-1 in attaching functionally relevant O-linked glycans to selectin ligands.