Multiple Hepatic Clearance Receptors Facilitate Elimination of Secretory Mucins that Can Enter the Bloodstream in Pathological States and Generate Platelet-Rich Microthrombi.

Epithelial cells that line hollow organs typically secrete mucins and their proteolytic fragments vectorially, into the lumen of the organ. Fragments of these large, heterogeneously O-glycosylated molecules can enter the blood stream during injury, inflammation or malignancy involving such organs. We have previously shown that intravenous injection of human carcinoma mucin fragments into mice triggered a “Trousseau”-like syndrome consisting of extensive formation of platelet- and leukocyte-rich microthrombi that were thrombin-independent, but L-and P-selectin-dependent and heparin-sensitive (Wahrenbrock et al., 2003, J Clin Invest, 112, 853–62). Thus, we hypothesized that mechanisms should exist to clear such mucin fragments when they enter the bloodstream in various pathological states. Indeed, intravenously injected radiolabeled mucin fragments had a circulating half-life of ~1 minute in mice, due to rapid and specific clearance by liver reticuloendothelial cells. Competition of uptake by inhibitors of known glycan-recognizing hepatic clearance receptors showed that several overlapping and non-overlapping systems work in concert to remove mucin fragments from the circulation. The systems involved include the hepatic asialoglycoprotein receptor, the macrophage Gal/GalNAc and Mannose receptors, and the endothelial S4GGnM and hyaluronan receptors. Studies of genetically deficient mice, and competition studies amongst various differently glycosylated mucins confirm this result. Thus, multiple hepatic clearance receptors collaborate to varying degrees to ensure elimination of the many polydisperse and differentially glycosylated forms of secretory mucins that might enter the blood circulation from various hollow organs, thus limiting their ability to cause pathology involving disseminated platelet and leukocyte aggregation. This process could also potentially modulate circulating levels of mucin epitopes that are sometimes used as diagnostic criteria in cancer (e.g., CA125, CA19-9 etc.). Furthermore, it can explain why mucin-type clustered O-glycosylation is very uncommon on circulating plasma proteins.