Sialylation on O-glycans protects platelets from clearance by liver Kupffer cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 31; pp. 8360 - 8365
• Main Authors: Li, Yun, Fu, Jianxin, Ling, Yun, Yago, Tadayuki, McDaniel, J. Michael, Song, Jianhua, Bai, Xia, Kondo, Yuji, Qin, Yannan, Hoover, Christopher, McGee, Samuel, Shao, Bojing, Liu, Zhenghui, Sonon, Roberto, Azadi, Parastoo, Marth, Jamey D., McEver, Rodger P., Ruan, Changgeng, Xia, Lijun
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 01.08.2017
• Subjects: Accumulation; Animals; Asialoglycoprotein Receptor - metabolism; Biological Sciences; Blood platelets; Blood Platelets - metabolism; Cells; Galactosyltransferases - genetics; Glycosylation; Hepatocytes; Hepatocytes - metabolism; Homeostasis - physiology; Kupffer cells; Kupffer Cells - metabolism; Lectins, C-Type - metabolism; Liver; Liver - metabolism; Membrane proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mucin; N-Acetylneuraminic Acid - metabolism; Phagocytosis; Platelets; Polysaccharides; Polysaccharides - metabolism; Proteins; Rodents; Sialic acids; Thrombocytopenia - pathology; O-glycan; Kupffer cell; clearance; platelet
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1707662114

Most platelet membrane proteins are modified by mucin-type core 1-derived glycans (O-glycans). However, the biological importance of O-glycans in platelet clearance is unclear. Here, we generated mice with a hematopoietic cell-specific loss of O-glycans (HC C1galt1 −/−). These mice lack O-glycans on platelets and exhibit reduced peripheral platelet numbers. Platelets from HC C1galt1 −/− mice show reduced levels of α-2,3-linked sialic acids and increased accumulation in the liver relative to wild-type platelets. The preferential accumulation of HC C1galt1 −/− platelets in the liver was reduced in mice lacking the hepatic asialoglycoprotein receptor [Ashwell–Morell receptor (AMR)]. However, we found that Kupffer cells are the primary cells phagocytosing HC C1galt1 −/− platelets in the liver. Our results demonstrate that hepatic AMR promotes preferential adherence to and phagocytosis of desialylated and/or HC C1galt1 −/− platelets by the Kupffer cell through its C-type lectin receptor CLEC4F. These findings provide insights into an essential role for core 1 O-glycosylation of platelets in their clearance in the liver.