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Results for “Mannose Receptor”

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At least 19 recordsLinked to original sources

PubMed2006

Carbohydrate-independent recognition of collagens by the macrophage mannose receptor.

Mannose receptor (MR) is the best characterised member of a family of four endocytic molecules that share a common domain structure; a cysteine-rich (CR) domain, a fibronectin-type II (FNII) domain and tandemly arranged C-type lectin-like domains (CTLD, eight in the case of MR). Two distinct lectin activities have been described for MR. The CR domain recognises sulphated carbohydrates while the CTLD mediate binding to mannose, fucose or N-acetylglucosamine. FNII domains are known to be important for collagen binding and this has been studied in the context of two members of the MR family, Endo180 and the phospholipase A2 receptor. Here, we have investigated whether the broad and effective lectin activity mediated by the CR domain and CTLD of MR is favoured to the detriment of FNII-mediated interaction(s). We show that MR is able to bind and internalise collagen in a carbohydrate-independent manner and that MR deficient macrophages have a marked defect in collagen IV and gelatin internalisation. These data have major implications at the molecular level as there are now three distinct ligand-binding sites described for MR. Furthermore our findings extend the range of endogenous ligands recognised by MR, a molecule firmly placed at the interface between homeostasis and immunity.

Animals↗

PubMed1998

Characterization of a rat alveolar macrophage cell line that expresses a functional mannose receptor.

The mannose receptor is a single polypeptide transmembrane glycoprotein expressed on the surface of macrophages that binds and internalizes soluble and particulate ligands. Physiological ligands for this receptor are pathogens, such as mycobacteria, and extracellular acid hydrolases and peroxidases. Expression of the mannose receptor is tightly linked to the functional state of the macrophage: the receptor appears during differentiation, is increased by macrophage deactivating agents, and is reduced in the presence of macrophage activating agents. Studies of the mechanisms underlying these regulatory processes have been hampered by the lack of a stable cell line that expresses a functional and appropriately regulated mannose receptor. In this study we describe expression and modulation of the mannose receptor by the rat alveolar cell line NR8383. Similar amounts of the mannose receptor ligand horseradish peroxidase were internalized by both NR8383 cells and alveolar macrophages. In addition, NR8383 cells expressed immunoreactive mannose receptor protein and mannose receptor mRNA as detected by Northern analysis. Regulation studies showed that mannose receptor expression was regulated at the levels of activity, protein, and mRNA in NR8383 cells similarly to regulation in primary rat macrophages. In addition, NR8383 cells could be successfully transfected with a luciferase reporter gene, providing the transfectable, mannose receptor-positive macrophage cell line. These results support the hypothesis that NR8383 cells potentially represent the best current macrophage cell line for studying various aspects of macrophage function, and are particularly critical in studies of regulation of the mannose receptor, a key receptor in host defense and immune regulation.

Animals↗

PubMed2006

Structural model for the mannose receptor family uncovered by electron microscopy of Endo180 and the mannose receptor.

The mannose receptor family comprises four members in mammals, Endo180 (CD280), DEC-205 (CD205), phospholipase A(2) receptor (PLA(2)R) and the mannose receptor (MR, CD206), whose extracellular portion contains a similar domain arrangement: an N-terminal cysteine-rich domain (CysR) followed by a single fibronectin type II domain (FNII) and 8-10 C-type lectin-like domains (CTLDs). These proteins mediate diverse functions ranging from extracellular matrix turnover through collagen uptake to homeostasis and immunity based on sugar recognition. Endo180 and the MR are multivalent transmembrane receptors capable of interacting with multiple ligands; in both receptors FNII recognizes collagens, and a single CTLD retains lectin activity (CTLD2 in Endo180 and CTLD4 in MR). It is expected that the overall conformation of these multivalent molecules would deeply influence their function as the availability of their binding sites could be altered under different conditions. However, conflicting reports have been published on the three-dimensional arrangement of these receptors. Here, we have used single particle electron microscopy to elucidate the three-dimensional organization of the MR and Endo180. Strikingly, we have found that both receptors display distinct three-dimensional structures, which are, however, conceptually very similar: a bent and compact conformation built upon interactions of the CysR domain and the lone functional CTLD. Biochemical and electron microscopy experiments indicate that, under a low pH mimicking the endosomal environment, both MR and Endo180 experience large conformational changes. We propose a structural model for the mannose receptor family where at least two conformations exist that may serve to regulate differences in ligand selectivity.

Hydrogen-Ion Concentration↗

PubMed1987

Generation of macrophage variants with 5-azacytidine: selection for mannose receptor expression.

Mannose receptors are expressed only in primary macrophages. Established macrophage-derived cell lines, although apparently possessing the potential to synthesize mannose receptors, do not express them on their plasma membranes. Using the drug 5-Azacytidine, mannose receptor expression was induced in the macrophage-derived mouse cell line J774. Receptor positive cells were sorted through a fluorescent activated cell sorter (FACS) prior to cloning. Clones were isolated which continuously express mannose receptors in culture. These macrophages were able to endocytose beta-glucuronidase and phagocytose yeast particles via mannose receptors. Secretion of the lysosomal enzyme beta-hexosaminidase was also reduced in proportion to the degree of mannose receptor expression.

Animals↗

PubMed1993

Structural requirements for high affinity binding of complex ligands by the macrophage mannose receptor.

The mannose receptor of macrophage and hepatic endothelial cells discriminates between endogenous and exogenous sugar-bearing structures. Previous competition studies have indicated that the receptor binds the monosaccharides mannose, fucose, and N-acetylglucosamine but displays much higher affinity for multivalent oligosaccharides, such as those found on the surface of potentially pathogenic microorganisms. The hydrodynamic properties of the receptor have been examined, revealing that the receptor is a monomer. This result suggests that multiple carbohydrate recognition domains (CRDs) in the extracellular domain of a single receptor polypeptide cooperate to achieve high affinity binding of complex ligands. In order to determine the importance of individual CRDs, properties of receptor segments containing groups of CRDs expressed in insect cells have been examined. The results indicate that two of the CRDs (4 and 5) form a protease-resistant, ligand-binding core but that five CRDs in tandem (4-8) are required to match the affinity of the intact receptor for yeast mannan. A consequence of the organization of the receptor is that both valency and geometry of glycoconjugates are important determinants of binding affinity.

Animals↗

PubMed1994

Dexamethasone blocks the interferon-gamma-mediated downregulation of the macrophage mannose receptor.

The macrophage mannose receptor is highly susceptible to modulation by a variety of proinflammatory and antiinflammatory agents. Previous studies have demonstrated that mannose receptor activity is dramatically increased in rat bone marrow-derived macrophages by dexamethasone treatment and decreased following incubation with interferon-gamma (IFN-gamma). Regulation by both agents occurs at least in part by alteration of mannose receptor mRNA levels. In the present study, we have investigated the ability of dexamethasone to block mannose receptor downregulation in rat marrow macrophages by IFN-gamma. Incubation of rat macrophages with IFN-gamma resulted in downregulation of mannose receptor activity, receptor synthesis, and mRNA levels, with no change in turnover rate of the receptor. IFN-gamma appeared to act at least partially through the generation of nitric oxide: inclusion of the nitric oxide inhibitor N-monomethyl arginine inhibited the IFN-gamma-induced effects on the mannose receptor by approximately 50%. When cells were coincubated with dexamethasone plus IFN-gamma, dexamethasone blocked the decrease in mannose receptor activity, synthesis, and mRNA. Additionally, dexamethasone inhibited nitric oxide production in response to IFN-gamma. These results suggest that mannose receptor expression is downregulated by IFN-gamma by at least two mechanisms: a decrease in mannose receptor mRNA levels and inhibition involving the production of nitric oxide. Dexamethasone has the capability of blocking the effect of IFN-gamma on mannose receptor expression through inhibition of IFN-gamma-mediated downregulation of mannose receptor transcription and/or inhibition of IFN-gamma-mediated induction of nitric oxide production.

Animals↗

PubMed2001

[Mannose receptor].

The mannose receptor (MR) is a calcium-dependent C-type lectin that is expressed on some macrophages, immature dendritic cells, endothelial, and epithelial cells. The most important feature of MR is the capability to distinguish self from non-self molecules through the interaction of multiple CRDs. The purpose of the short review is to summarise the structural and functional properties of MR.

Animals↗

PubMed2005

Glycosylation influences the lectin activities of the macrophage mannose receptor.

The mannose receptor (MR) is a heavily glycosylated endocytic receptor that recognizes both mannosylated and sulfated ligands through its C-type lectin domains and cysteine-rich (CR) domain, respectively. Differential binding properties have been described for MR isolated from different sources, and we hypothesized that this could be due to altered glycosylation. Using MR transductants and purified MR, we demonstrate that glycosylation differentially affects both MR lectin activities. MR transductants generated in glycosylation mutant cell lines lacked most mannose internalization activity, but could internalize sulfated glycans. Accordingly, purified MR bearing truncated Man5-GlcNAc2 glycans (Man5 -MR) or non-sialylated complex glycans (SA0-MR) did not bind mannosylated glycans, but could recognize SO4-3-Gal in vitro. Additional studies showed that, although mannose recognition was largely independent of the oligomerization state of the protein, recognition of sulfated carbohydrates was mostly mediated by self-associated MR and that, in SA0-MR, there was a higher proportion of oligomeric MR. These results suggest that self-association could lead to multiple presentation of CR domains and enhanced avidity for sulfated sugars and that non-sialylated MR is predisposed to oligomerize. Therefore, the glycosylation of MR, terminal sialylation in particular, could influence its binding properties at two levels. (i) It is required for mannose recognition; and (ii) it modulates the tendency of MR to self-associate, effectively regulating the avidity of the CR domain for sulfated sugar ligands.

Animals↗

PubMed2000

Structure of a C-type carbohydrate recognition domain from the macrophage mannose receptor.

The mannose receptor of macrophages and liver endothelium mediates clearance of pathogenic organisms and potentially harmful glycoconjugates. The extracellular portion of the receptor includes eight C-type carbohydrate recognition domains (CRDs), of which one, CRD-4, shows detectable binding to monosaccharide ligands. We have determined the crystal structure of CRD-4. Although the basic C-type lectin fold is preserved, a loop extends away from the core of the domain to form a domain-swapped dimer in the crystal. Of the two Ca(2+) sites, only the principal site known to mediate carbohydrate binding in other C-type lectins is occupied. This site is altered in a way that makes sugar binding impossible in the mode observed in other C-type lectins. The structure is likely to represent an endosomal form of the domain formed when Ca(2+) is lost from the auxiliary calcium site. The structure suggests a mechanism for endosomal ligand release in which the auxiliary calcium site serves as a pH sensor. Acid pH-induced removal of this Ca(2+) results in conformational rearrangements of the receptor, rendering it unable to bind carbohydrate ligands.

Amino Acid Sequence↗

PubMed2001

The molecular mechanism of sulfated carbohydrate recognition by the cysteine-rich domain of mannose receptor.

The mannose receptor (MR) binds foreign and host ligands through interactions with their carbohydrates. Two portions of MR have distinct carbohydrate recognition properties. One is conferred by the amino-terminal cysteine-rich domain (Cys-MR), which plays a critical role in binding sulfated glycoproteins including pituitary hormones. The other is achieved by tandemly arranged C-type lectin domains that facilitate carbohydrate-dependent uptake of infectious microorganisms. This dual carbohydrate binding specificity enables MR to bind ligands by interacting with both sulfated and non-sulfated polysaccharide chains. We previously determined crystal structures of Cys-MR complexed with 4-SO(4)-N-acetylglucosamine and with an unidentified ligand resembling Hepes (N-[2-hydroxyethyl]piperazine-N'-[2-ethanesulfonic acid]). In continued efforts to elucidate the mechanism of sulfated carbohydrate recognition by Cys-MR, we characterized the binding affinities between Cys-MR and potential carbohydrate ligands using a fluorescence-based assay. We find that Cys-MR binds sulfated carbohydrates with relatively high affinities (K(D)=0.1 mM to 1.0 mM) compared to the affinities of other lectins. Cys-MR also binds Hepes with a K(D) value of 3.9 mM, consistent with the suggestion that the ligand in the original Cys-MR crystal structure is Hepes. We also determined crystal structures of Cys-MR complexed with 3-SO(4)-Lewis(x), 3-SO(4)-Lewis(a), and 6-SO(4)-N-acetylglucosamine at 1.9 A, 2.2 A, and 2.5 A resolution, respectively, and the 2.0 A structure of Cys-MR that had been treated to remove Hepes. The conformation of the Cys-MR binding site is virtually identical in all Cys-MR crystal structures, suggesting that Cys-MR does not undergo conformational changes upon ligand binding. The structures are used to rationalize the binding affinities derived from the biochemical studies and to elucidate the molecular mechanism of sulfated carbohydrate recognition by Cys-MR.

Acetylglucosamine↗

PubMed2000

HIV-1 Tat represses transcription from the mannose receptor promoter.

The mannose receptor is expressed on mature macrophages and immature dendritic cells, and functions to mediate phagocytosis of pathogens and capture of Ags for delivery to MHC class II-containing intracellular compartments. It has been previously reported that HIV-1-infected macrophages have reduced functions associated with the mannose receptor, including impaired Pneumocystis carinii phagocytosis and mannosylated albumin uptake. Several HIV-1-derived proteins including the Tat protein have been shown to transcriptionally repress host cell genes. The present study was undertaken to define the role of the HIV-1-derived protein Tat in HIV-mediated mannose receptor down-regulation. Cotransfection of the human macrophage cell line U937 with a Tat expression vector and a mannose receptor promoter-luciferase reporter construct resulted in down-regulation of mannose receptor promoter activity. This repression was targeted to the basal promoter. Expression of either one- or two-exon Tat resulted in decreased promoter activity. The addition of the transactivation response element (TAR) sequence enhanced the Tat-mediated repression. Down-regulation was also seen when transfected cells were treated with exogenously added Tat protein. These results are consistent with a mechanism whereby Tat reduces mannose receptor promoter activity by interfering with the host transcriptional initiation machinery, potentially resulting in decreased levels of surface mannose receptor available for Ag or pathogen capture.

Animals↗

PubMed1999

Mannose receptor and its putative ligands in normal murine lymphoid and nonlymphoid organs: In situ expression of mannose receptor by selected macrophages, endothelial cells, perivascular microglia, and mesangial cells, but not dendritic cells.

The mannose receptor (MR) has established roles in macrophage (Mphi) phagocytosis of microorganisms and endocytic clearance of host-derived glycoproteins, and has recently been implicated in antigen capture by dendritic cells (DCs) in vitro. MR is the founder member of a family of homologous proteins, and its recognition properties differ according to its tissue of origin. Given this heterogeneity and our recent discovery of a soluble form of MR in mouse serum, we studied the sites of synthesis of MR mRNA and expression of MR protein in normal mouse tissues. We demonstrate that synthesis and expression occur at identical sites, and that mature Mphi and endothelium are heterogeneous with respect to MR expression, additionally describing MR on perivascular microglia and glomerular mesangial cells. However, MR was not detected on DCs in situ, or on marginal zone or subcapsular sinus Mphi, both of which have MR-like binding activities. We also compared expression of MR to the binding of a recombinant probe containing the cysteine-rich domain of MR. We show that MR and its putative ligand(s) are expressed at nonoverlapping sites within lymphoid organs, consistent with a transfer function for soluble MR. Therefore, in addition to endocytic and phagocytic roles, MR may play an important role in antigen recognition and transport within lymphoid organs.

Animals↗

PubMed1994

The exon-intron structure and chromosomal localization of the mouse macrophage mannose receptor gene Mrc1: identification of a Ricin-like domain at the N-terminus of the receptor.

The macrophage mannose receptor is a transmembrane protein that is expressed on the surface of mature macrophages. The ectodomain of the receptor contains multiple domains, eight of which belong to the calcium-dependent C-type lectin family. The mannose receptor binds to carbohydrate polymers that have a high content of mannose. This property allows this protein to function as a phagocytic receptor that participates in first-line host defense against invading microorganisms. In this paper we describe the intron-exon structure of the mouse macrophage mannose receptor gene which was found to span at least 70 kilobases. We also report the localization of this gene, termed Mrc1, to mouse Chromosome 2. Like its human counterpart, Mrc1 contains 30 exons and 29 introns. A protein module that resembles a subdomain of the B chain of the plant lectin Ricin has been found within the N-terminal cysteine-rich domain of the mannose receptor.

3T3 Cells↗

PubMed1998

Role of carbohydrate and protein in the binding of tissue-type plasminogen activator to the human mannose receptor.

The 175-kDa mannose receptor is one of the receptors that mediates the clearance of tissue-type plasminogen activator (t-PA). The affinity of t-PA for the mannose receptor is much higher than the affinity of other high-mannose-type oligosaccharide-containing glycoproteins. In order to find an explanation for this high affinity, we studied the biochemical interaction of various forms of t-PA with the isolated human mannose receptor in several in vitro binding assays. t-PA showed a high affinity (Ki = 0.2 nM) for the mannose receptor and the interaction could be fully inhibited by mannan or polyclonal antibodies against the mannose receptor. The interaction was not affected by non-glycosylated t-PA. The high affinity differed slightly between t-PAs synthesized by various cell types (range Ki 0.2-0.7 nM) and between various glycoforms of t-PA. No statistically significant difference in affinity between t-PA and t-PA complexed to inhibitors was observed. In contrast to intact t-PA, a trypsin digest of t-PA had a low affinity (Ki = 0.5 microM) for the mannose receptor. Both intact and trypsin digests of the high-mannose-type oligosaccharide-containing glycoproteins ribonuclease B and ovalbumin had a low affinity (Ki 0.5-1.5 microM) for the mannose receptor. We conclude that neither protein-protein interactions, nor the complex-type oligosaccharides and the fucose residue on t-PA contribute significantly to the high-affinity binding of t-PA. We suggest that the conformation of the high-mannose-type oligosaccharide on t-PA is influenced by the protein moiety of t-PA in such a way that the oligosaccharide has a high affinity for the mannose receptor.

Binding, Competitive↗

PubMed1991

Monomeric IgG2a promotes maturation of bone-marrow macrophages and expression of the mannose receptor.

The macrophage mannose receptor, a 172-kDa lineage-specific glycoprotein, partakes in nonopsonin-mediated phagocytosis by recognition of terminal mannose residues on targeted particles. Because appearance of the receptor progresses with monocyte/macrophage differentiation, its expression is indicative of the maturational state of the cell. Monomeric IgG2a and IgG2b up-regulate mannose-receptor surface expression and biosynthesis by murine bone-marrow macrophage precursors as much as 7- to 12-fold in a dose-dependent manner. IgG2a accelerates macrophage mannose-receptor expression by several days during in vitro bone-marrow differentiation; however, treated and control cells ultimately express equivalent levels of receptor. Moreover, the effect is independent of cell cycle or ambient levels of colony-stimulating factor 1. The coinduction of another maturation-dependent lineage-specific antigen, F4/80, and the fact that macrophage precursors respond to IgG2a only within the first day of culture, indicate that the targeted cell is an early myelomonocytic precursor, responsive only during a short, early developmental window. The effect is specific for immunoglobulin molecules of the IgG2a and IgG2b subclasses and probably involves an Fc gamma-receptor signal-transduction pathway but not macrophage priming or activation. Most importantly, a paracrine mechanism of immunoglobulin-mediated bone-marrow macrophage differentiation is suggested by experiments in which basal levels of mannose-receptor expression are reduced by continual removal of B-cell-generated IgG from marrow cultures. Thus, IgG2a and IgG2b prompt mannose-receptor synthesis and bone-marrow macrophage differentiation and may, therefore, play a role in the regulation of macrophage differentiation in host defense.

Animals↗

PubMed1999

Multiple interactions between pituitary hormones and the mannose receptor.

The macrophage mannose receptor, which has a well-documented role in the innate immune system, has an additional function in the clearance of pituitary hormones. Clearance is mediated by the recognition of sulphated terminal N-acetylgalactosamine residues (SO(4)-4GalNAc) on the hormones. Previous studies with an SO(4)-4GalNAc-containing neoglycoprotein suggest that the SO(4)-4GalNAc-binding site is localized to the N-terminal cysteine-rich domain of the receptor, distinct from the mannose/N-acetylglucosamine/fucose-specific C-type carbohydrate-recognition domains (CRDs). The present study characterizes the binding of natural pituitary hormone ligands to a soluble portion of the mannose receptor consisting of the whole extracellular domain and to a truncated form containing the eight CRDs but lacking the N-terminal cysteine-rich domain and the fibronectin type II repeat. Both forms of the receptor show high-affinity saturable binding of lutropin and thyrotropin. Binding to the full-length receptor is dependent on pH and ionic strength and is inhibited effectively by SO(4)-4GalNAc but only partly by mannose. In contrast, binding to the truncated form of the receptor, which is also dependent on pH and ionic strength, is inhibited by mannose but not by SO(4)-4GalNAc. The results are consistent with the presence of an SO(4)-4GalNAc-specific binding site in the cysteine-rich domain of the mannose receptor but indicate that interactions between other sugars on the hormones and the CRDs are also important in hormone binding.

Acetylgalactosamine↗

PubMed2001

Novel hyperbranched glycomimetics recognized by the human mannose receptor: quinic or shikimic acid derivatives as mannose bioisosteres.

The mannose receptor mediates the internalization of a wide range of molecules or microorganisms in a pattern recognition manner. Therefore, it represents an attractive entry for specific drug, gene, or antigen delivery to macrophages and dendritic cells. In an attempt to design novel effective synthetic mannose receptor ligands, quinic and shikimic acid were selected as putative mannose mimics on the basis of X-ray crystallographic data from the related rat mannose-binding lectin. As the mannose receptor preferentially binds to molecules displaying several sugar residues, fluorescein-labeled cluster quinic and shikimic acid derivatives with valencies of two to eight were synthesized. Their mannose receptor mediated uptake was assayed on monocyte-derived human dendritic cells by cytofluorimetric analysis. Mannose-receptor specificity was further assessed by competitive inhibition assays with mannan, by confocal microscopy analysis, and by expression of the mannose receptor in transfected Cos-1 cells. Constructs derived from both quinic and shikimic acid were efficiently recognized by the mannose receptor with an optimum affinity for the molecules with a valency of four. As a result, commercially available quinic and shikimic acids appear as stable mannose bioisosteres, which should prove valuable tools for specific cell delivery.

Animals↗

PubMed1998

Reduced binding and phagocytosis of Pneumocystis carinii by alveolar macrophages from persons infected with HIV-1 correlates with mannose receptor downregulation.

The macrophage mannose receptor, a pattern recognition molecule and component of innate immunity, mediates binding and phagocytosis of Pneumocystis carinii and likely represents an important clearance mechanism in the lungs of immunocompetent hosts. The purpose of this study was to examine the ability of alveolar macrophages from HIV-infected individuals to bind and phagocytose P. carinii, and to investigate the role of the macrophage mannose receptor in mediating this interaction. Compared with healthy individuals, alveolar macrophage phagocytosis of P. carinii from HIV+ persons was reduced up to 74% (P = 0.02), primarily reflecting a reduction in the number of organisms associated with each macrophage (P = 0.019). Furthermore, macrophages from HIV+ individuals demonstrated up to an 80% (P < 0.05) reduction in mannose receptor surface expression and endocytosis. Mannose receptor affinity was unaltered, and mRNA levels were modestly reduced (P < 0.05). Cells from HIV+ individuals with CD4(+) counts < 200 cells/mm3 (representing individuals at high clinical risk for P. carinii pneumonia) demonstrated the lowest levels of P. carinii phagocytosis and mannose receptor endocytosis. In vitro HIV infection of alveolar macrophages from healthy individuals reduced mannose receptor endocytosis to 53.2% (P < 0.05) and P. carinii binding and phagocytosis to 67.4% (P < 0.05) of control. Our studies suggest that HIV infection may alter innate immunity in the lungs, and that impaired alveolar macrophage mannose receptor-mediated binding and phagocytosis of P. carinii may contribute to the susceptibility of HIV-infected individuals to this opportunistic pulmonary pathogen.

Bronchoalveolar Lavage Fluid↗