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

Abstract

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 <i>C1galt1</i>^<i>-/-</i> ). These mice lack O-glycans on platelets and exhibit reduced peripheral platelet numbers. Platelets from HC <i>C1galt1</i>^<i>-/-</i> 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 <i>C1galt1</i>^<i>-/-</i> 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 <i>C1galt1</i>^<i>-/-</i> platelets in the liver. Our results demonstrate that hepatic AMR promotes preferential adherence to and phagocytosis of desialylated and/or HC <i>C1galt1</i>^<i>-/-</i> 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.