Kupffer cell receptor CLEC4F is important for the destruction of desialylated platelets in mice

Abstract

The liver has recently been identified as a major organ for destruction of desialylated platelets. However, the underlying mechanism remains unclear. Kupffer cells, which are professional phagocytic cells in the liver, comprise the largest population of resident tissue macrophages in the body. Kupffer cells express a C-type lectin receptor, CLEC4F, that recognizes desialylated glycans with an unclear in vivo role in mediating platelet destruction. In this study, we generated a CLEC4F-deficient mouse model (Clec4f−/−) and found that CLEC4F was specifically expressed by Kupffer cells. Using the Clec4f−/− mice and a newly generated platelet-specific reporter mouse line, we revealed a critical role for CLEC4F on Kupffer cells in mediating destruction of desialylated platelets in the liver in vivo. Platelet clearance experiments and ultrastructural analysis revealed that desialylated platelets were phagocytized predominantly by Kupffer cells in a CLEC4F-dependent manner in mice. Collectively, these findings identify CLEC4F as a Kupffer cell receptor important for the destruction of desialylated platelets induced by bacteria-derived neuraminidases, which provide new insights into the pathogenesis of thrombocytopenia in disease conditions such as sepsis.

The GPIb-IX complex on platelets: insight into its novel physiological functions affecting immune surveillance, hepatic thrombopoietin generation, platelet clearance and its relevance for cancer development and metastasis

“…Next to the AMR-mediated platelet clearance, also the integrin α M β 2 and C-type lectin receptor, CLEC4F, on Kupffer cells have an impact on platelet phagocytosis as an alternative pathway for the elimination of senescent platelets from the circulation. The integrin α M β 2 as well as CLEC4F recognize exposed and irreversibly clustered β- N -acetylglucosamine/ N -acetylgalactosamine residues of N -linked glycans on GPIbα which initiates subsequent phagocytosis [ 20 , 124 , 125 ]. Furthermore, it is becoming increasingly clear that the Macrophage galactose lectin (MGL) supports AMR-mediated clearance by Kupffer cells [ 126 ].…”

Novel therapies for immune thrombocytopenia

“…The exact mechanism by which desialylated platelets are removed from the circulation by the liver remains unclear. It has been proposed in murine models that the microvilli of hepatocytes extrude through the overlying endothelial cells allowing direct access to the vascular space (Fig 3); the AMRs on these villi bind the desialylated platelets and pass them to adjacent Kupffer cells through a different type C lectin receptor (CLEC4F) where they are phagocytosed and destroyed 28,121‐123 …”

“…Upon treatment of mice with neuraminidase, the desialylated platelets are cleared entirely by the Kupffer cells with none being found in hepatocytes; mice with homozygous deficiency of CLEC4F develop much less thrombocytopenia after neuraminidase treatment. This has led to a modified model (Fig 3) of clearance of desialylated platelets in which the Kupffer cell is the main site of platelet adhesion and phagocytosis possibly with some collaboration with the MGL and hepatocyte AMR 122,123 . But if overwhelmed, hepatocyte clearance may also ensue 125 …”

“…It has been proposed in murine models that the microvilli of hepatocytes extrude through the overlying endothelial cells allowing direct access to the vascular space (Fig 3 ); the AMRs on these villi bind the desialylated platelets and pass them to adjacent Kupffer cells through a different type C lectin receptor (CLEC4F) where they are phagocytosed and destroyed. 28,[121][122][123] Amounts of 80-90% of body macrophages are in the liver and Kupffer cells comprise 15% of the liver volume and surround the vascular liver sinusoids. Although possessing only small amounts of AMR, 123 they contain the macrophage galactose lectin (MGL) as well as the unique C-type lectin, CLEC4F (also called Kupffer cell receptor, KCR).…”

“…28,[121][122][123] Amounts of 80-90% of body macrophages are in the liver and Kupffer cells comprise 15% of the liver volume and surround the vascular liver sinusoids. Although possessing only small amounts of AMR, 123 they contain the macrophage galactose lectin (MGL) as well as the unique C-type lectin, CLEC4F (also called Kupffer cell receptor, KCR). CLEC4F binds GalNAc, Gal and fucose and is found only on Kupffer cells, even those in humans.…”