The asialoglycoprotein receptor (ASGPR) is a C-type lectin essentially unique to hepatocytes that plays a central role in the clearance of circulating desialylated glycoproteins through calcium-dependent endocytosis and lysosomal
degradation.7, learn more 8 The receptor is a heterooligomeric molecule composed of two polypeptides, designated as major (ASGPR-1) and minor (ASGPR-2) subunits.7-9 It is of note that due to its organ-restricted expression, a pathogenic role of immune responses directed against ASGPR in certain forms of autoimmune and viral hepatitis is postulated.9-12 In fact, the invariable appearance of anti-ASGPR autoantibodies induced by hepadnaviral infection in the woodchuck model of hepatitis B13 are capable of inducing complement-mediated hepatocellular injury14 and their presence can modify the severity and outcome of experimental hepadnaviral hepatitis.15 Although the most recognized role for ASGPR is the removal of terminally desialylated glycoproteins, it has been proposed that this website ASGPR may also facilitate the trapping of activated lymphocytes. Specifically, activated T cells that express the B220 epitope, a sialic acid-depleted form of CD45,
accumulate within the livers of CD95-deficient mice.16 It was proposed that recognition of activated T lymphocytes could be responsible for the hepatic-retention and ultimately cell removal by way of
an apoptotic mechanism that is at least partly due to the death signal imparted by CD95.16, 17 Although it has been shown that activated T cells may undergo selleck products apoptosis within the liver, the recent identification of hepatocyte-mediated cell killing2, 3 and the data summarized above imply that hepatocytes may play a role in this process. Pursuing this notion, we investigated whether ASGPR may directly contribute to recognition and removal of cells by hepatocytes, particularly CD4+ T lymphocytes. The present study showed that desialylation of the cell surface glycoproteins leads to enhanced hepatocyte-mediated apoptosis of target cells and that disruption of the ASGPR binding activity by receptor blockade using a soluble ligand or small interfering RNA (siRNA)-mediated knockdown of ASGPR expression results in significantly reduced rates of target cell killing by hepatocytes. Also, our study provides the first evidence that hepatocytes can eliminate activated T lymphocytes brought into contact with their surface. ASF, asialofetuin; ASGPR, asialoglycoprotein receptor; CD95L, CD95 ligand; CTL, cytotoxic T lymphocytes; MHC, major histocompatibility complex; NK, natural killer cells; PBMC, peripheral blood mononuclear cell; PHA, phytohemagglutinin; RT-PCR, reverse-transcription polymerase chain reaction; siRNA, small interfering RNA.