Molecular characterization of the human macrophage mannose receptor: demonstration of multiple carbohydrate recognition-like domains and phagocytosis of yeasts in Cos-1 cells.

Abstract

SummaryThe macrophage mannose receptor is an integral membrane protein expressed on the surface of tissue macrophages . After ligation ofmannose-rich glycoconjugates or pathogens, the receptor mediates endorytosis and phagocytosis of the bound ligands by macrophages. The cDNAderived primary structure of the mannose receptor predicts a cysteine-rich NH2-terminal domain, followed by a fibronectin type II region. The remainder of the ectodomain is comprised of eight carbohydrate recognition-like domains, followed by a transmembrane region, and a cytoplasmic tail. Transfection of the mannose receptor cDNA into Cos-I cells is necessary for receptor-mediated endorytosis of mannose-rich glycoconjugate as well as phagocytosis of yeasts. Deletion of the cytoplasmic tail results in a mutant receptor that is able to bind but not ingest the ligated pathogens, suggesting that the signal for phagocytosis is contained in the cytoplasmic tail.P lasma clearance and cell uptake experiments (1) indicated the existence ofa receptor that bound glycoproteins bearing high mannose chains. Receptor activity was especially evident in the liver and spleens, although most other tissues were also positive. Subsequent experiments have established that the mannose receptor is expressed on the cell surface of tissue macrophages which reside in a wide anatomical distribution throughout most organs (2) . Although originally defined by its ability to mediate endorytosis ofmannosylated or fucosylated glycoproteins, the mannose receptor's predominant role appears to be in host defense. The receptor engages yeasts (3) and parasites (4) directly resulting in the engulfment of these particles and the release ofbiologically active secretory products like reactive oxygen intermediates (5), arachidonate metabolites (6), neutral proteinases (7), and monokines like IM and tumor necrosis factor (8) . As circulating monocytes do not express the mannose receptor on their cell surface (9), the functional role for the mannose receptor appears to be on tissue macrophages, which in addition to their localization in the reticular endothelial system line the alveolus and form a reticular network beneath epithelial surfaces in the skin, the gastrointestinal tract, kidney, and placenta (10). These sites are the portals of maximum antigen load and underscore the role for the mannose receptor in first line host defense.Recent experiments suggest that a circulating hepatocytederived serum mannose-binding protein is the functional serum equivalent of the tissue macrophage mannose receptor. The human mannose-binding protein (MBP)l is an acute-phase reactant (11) that binds certain viruses (12) and other mannose rich pathogens (13). Mannose-binding proteins after engaging organisms mediate attachment, uptake, and killing of opsonized bacteria by circulating phagocytes that do not express the mannose receptor (13). Underlying structural similarity between the MBP and the mannose receptor, thereby explaining their functional equivalence, was suggested by the discovery that h...

Synergistic regulation of Pseudomonas aeruginosa‐induced cytokine production in human monocytes by mannose receptor and TLR2

“…MR, a well-characterized receptor, has been reported to bind a wide variety of pathogens including Candida albicans [30], Leishmania donovani [38], Pneumocystis carinii [39], and Mycobacterium tuberculosis [40]. Moreover MR has been recognized as a phagocytic receptor of non-opsonized P. aeruginosa bacteria [33].…”

“…In order to test the specificity of MR blocking, we used well-characterized ligands or nonspecific competitors of MR, before adding stimulants. Soluble mannan, a competitive inhibitor of MR [30,31], caused a 40% inhibition of TNF-a production by viable P. aeruginosa bacteria. In contrast, laminarin, a competitive inhibitor of b-glycan receptor [32], caused a small, but not a statistically significant inhibition, and the isotype-matched non-specific Ab had no effect (data not shown).…”

The Dendritic Cell-Specific Adhesion Receptor DC-SIGN Internalizes Antigen for Presentation to T Cells

“…Langerin contains a single CRD and functions on skin epidermal Langerhans cells (LCs) as an endocytic receptor that is associated with and induces formation of Birbeck granules (11,12). The MR, highly expressed on immature DCs and macrophages, has eight potential CRDs, of which two were shown to be functional for binding end-standing mannose groups on a variety of pathogens and Ags, illustrating its role in innate immunity (13,14). The MR is constitutively internalized from the cell surface into early endosomes and recycles back to the plasma membrane (15).…”

The mannose receptor, localization and role in the clearance of tissue-type plasminogen activator

“…Waarschijnlijk beinvloedt het eiwit van t-PA de confo rm atie van het hoog mannose-type suiker op t-PA zodanig dat de het suiker polymeer aan meerdere suiker herkenningsdomeinen van de mannose receptor kan binden waardoor intact t-PA een hoge affiniteit heeft voor de mannose receptor. De bindingsassay met geisoleerde humane mannose receptor werd in verdere studies als een in vitro meetsysteem gebruikt om de effectiviteit van remmers van de mannose receptor-t-PA binding te bepalen (zie hoofdstuk 3,6,7,8).…”

“…7 We wanted to know whether an inhibitor of mannose receptor-mediated t-PA degradation would increase the plasma concentrations of endogenous t-PA in man and thereby prevent thrombosis in man. For this we searched the literature for potential ligands/inhibitors ol the mannose receptor which have been shown to increase plasma t-PA concentrations in man.…”