Mannose receptor

{{Short description|Protein family}} {{cs1 config|name-list-style=vanc}} {{Pfam_box | Symbol = MMR | Name = Macrophage mannose receptor | image = | width = | caption = | InterPro= | SMART= | PROSITE = | SCOP = | TCDB = | OPM family= | OPM protein= | Pfam= | PDB= | Membranome family= 56 }} {{infobox protein |Name=mannose receptor, C type 1 |caption= |image= |width= |HGNCid=7228 |Symbol=MRC1 |AltSymbols= CD206 |EntrezGene=4360 |OMIM=153618 |RefSeq=NM_002438 |UniProt=P22897 |PDB= |ECnumber= |Chromosome=10 |Arm=p |Band=13 |LocusSupplementaryData= }} {{infobox protein |Name=mannose receptor, C type 2 |caption= |image= |width= |HGNCid=16875 |Symbol=MRC2 |AltSymbols= CD280 |EntrezGene=9902 |OMIM= |RefSeq=NM_006039 |UniProt=Q9UBG0 |PDB= |ECnumber= |Chromosome=17 |Arm=q |Band=23 |LocusSupplementaryData= }} The '''mannose receptor''' ('''C'''luster of '''D'''ifferentiation 206, '''CD206''') is a C-type lectin primarily present on the surface of macrophages, immature dendritic cells and liver sinusoidal endothelial cells, but is also expressed on the surface of skin cells such as human dermal fibroblasts and keratinocytes.<ref name="pmid11511295">{{cite journal |vauthors=Szolnoky G, Bata-Csörgö Z, Kenderessy AS, Kiss M, Pivarcsi A, Novák Z, Nagy Newman K, Michel G, Ruzicka T, Maródi L, Dobozy A, Kemény L | title = A mannose-binding receptor is expressed on human keratinocytes and mediates killing of ''Candida albicans'' | journal = Journal of Investigative Dermatology | volume = 117 | issue = 2 | pages = 205–13 |date=August 2001 | pmid = 11511295 | doi = 10.1046/j.1523-1747.2001.14071.x | doi-access = free | hdl = 2437/105199 | hdl-access = free }}</ref><ref name="pmid10683150">{{cite journal |vauthors=Sheikh H, Yarwood H, Ashworth A, Isacke CM | title = Endo180, an endocytic recycling glycoprotein related to the macrophage mannose receptor is expressed on fibroblasts, endothelial cells and macrophages and functions as a lectin receptor | journal = Journal of Cell Science | volume = 113 | issue = 6| pages = 1021–32 |date=March 2000 | doi = 10.1242/jcs.113.6.1021 | pmid = 10683150 }}</ref> It is the first member of a family of endocytic receptors that includes Endo180 (CD280), M-type PLA2R, and DEC-205 (CD205).<ref name="East2002">{{cite journal |vauthors=East L, Isacke CM | title = The mannose receptor family | journal = Biochimica et Biophysica Acta (BBA) - General Subjects | volume = 1572 | issue = 2–3 | pages = 364–86 | year = 2002 | pmid = 12223280 | doi = 10.1016/S0304-4165(02)00319-7 }}</ref>

The receptor recognises terminal mannose, ''N''-acetylglucosamine and fucose residues on glycans attached to proteins <ref name="Schlesinger1978">{{cite journal |vauthors=Schlesinger PH, Doebber TW, Mandell BF, White R, DeSchryver C, Rodman JS, Miller MJ, Stahl P | title = Plasma clearance of glycoproteins with terminal mannose and N-acetylglucosamine by liver non-parenchymal cells. Studies with beta-glucuronidase, N-acetyl-β-D-glucosaminidase, ribonuclease B and agalacto-orosomucoid | journal = Biochemical Journal | volume = 176 | issue = 1 | pages = 103–9 | year = 1978 | pmid = 728098 | pmc = 1186209 | doi = 10.1042/bj1760103}}</ref> found on the surface of some microorganisms, playing a role in both the innate and adaptive immune systems. Additional functions include clearance of glycoproteins from circulation, including sulphated glycoprotein hormones and glycoproteins released in response to pathological events.<ref name="Lee2002">{{cite journal |vauthors=Lee SJ, Evers S, Roeder D, Parlow AF, Risteli J, Risteli L, Lee YC, Feizi T, Langen H, Nussenzweig MC | title = Mannose receptor-mediated regulation of serum glycoprotein homeostasis | journal = Science | volume = 295 | issue = 5561 | pages = 1898–901 | year = 2002 | pmid = 11884756 | doi = 10.1126/science.1069540 | bibcode = 2002Sci...295.1898L | s2cid = 31432874 }}</ref> The mannose receptor recycles continuously between the plasma membrane and endosomal compartments in a clathrin-dependent manner.<ref name="Gazi2009">{{cite journal |vauthors=Gazi U, Martinez-Pomares L | title = Influence of the mannose receptor in host immune responses | journal = Immunobiology | volume = 214 | issue = 7 | pages = 554–61 | year = 2009 | pmid = 19162368 | doi = 10.1016/j.imbio.2008.11.004 }}</ref>

==Structure==

===Domain organisation=== thumb|upright=1.5|right|alt=The extracellular portion of the mannose receptor contains an N-terminal cystein-rich domain, a fibronectin type II domain and 8 C-type carbohydrate recognition domains. This is followed by a transmembrane region and a short cytoplasmic C-terminal tail|Domain organisation of the mannose receptor, adapted from ''Introduction to Glycobiology''.<ref name="IntroToGlycobiology">{{Cite book |vauthors=Taylor M, Drickamer K | title=Introduction to Glycobiology | publisher=Oxford University Press | year=2011 | isbn=978-0-19-956911-3}} </ref>

The mannose receptor is a type I transmembrane protein, with an extracellular N-terminus and an intracellular C-terminus. It is first synthesised as an inactive precursor, but is proteolytically cleaved to its active form in the Golgi apparatus.<ref name="Stahl1998"/> In general, The extracellular portion of the receptor is composed of 8 consecutive C-type carbohydrate recognition domains (CRDs) closest to the plasma membrane, followed by a single fibronectin type II repeat domain and an N-terminal cysteine-rich domain. The cytoplasmic tail is not capable of signal transduction in isolation, since it lacks the appropriate signaling motifs.<ref name="Martinez2012">{{cite journal | author = Martinez-Pomares L | title = The mannose receptor | journal = Journal of Leukocyte Biology | volume = 92 | issue = 6 | pages = 1177–86 | year = 2012 | pmid = 22966131 | doi = 10.1189/jlb.0512231 | s2cid = 27512588 | doi-access = free }}</ref>

===N-terminal cysteine-rich domain===

The N-terminal cysteine-rich domain is homologous to the ricin B chain and binds to sulphated sugar moieties, with particularly high affinity for ''N''-Acetylgalactosamine and galactose residues sulphated at positions 3 and 4 of their pyranose rings.<ref name="Fiete1998">{{cite journal |vauthors=Fiete DJ, Beranek MC, Baenziger JU | title = A cysteine-rich domain of the "mannose" receptor mediates GalNAc-4-SO4 binding | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 5 | pages = 2089–93 |date=March 1998 | pmid = 9482843 | pmc = 19259 | doi = 10.1073/pnas.95.5.2089| bibcode = 1998PNAS...95.2089F | doi-access = free }}</ref>

Other ligands include chondroitin sulfates A and B, as well as sulphated Lewisx and Lewisa structures.<ref name="Gazi2009"/> The mannose receptor is the only member of the family in which this domain is functional.<ref name="Lee2002"/> thumb|left|alt=Pymol image of the mannose receptor N-terminal cystein-rich domain bound to its sulphated N-Acetylgalactosamine ligand. The sulphated ligand fits snugly into a pocket on the surface of the cysteine-rich domain|The mannose receptor N-terminal cysteine-rich domain (pink) bound to its sulphated ''N''-Acetylgalactosamine ligand (cyan). PBD ID: 1DQO

===Fibronectin type II repeat domain=== The fibronectin type II repeat domain is conserved amongst all members of the mannose receptor family. Collagens I-IV bind this region with high affinity, while collagen V binds only weakly. Through this domain, the mannose receptor internalises collagen in macrophages and liver sinusoidal cells, independent of the lectin activity of the receptor.<ref name="Martinez2012"/> Along with the N-terminal cysteine-rich domain, this domain is the most highly conserved between mice and humans (92%).<ref name="Stahl1998">{{cite journal |vauthors=Stahl PD, Ezekowitz RA | title = The mannose receptor is a pattern recognition receptor involved in host defense | journal = Current Opinion in Immunology | volume = 10 | issue = 1 | pages = 50–5 | year = 1998 | pmid = 9523111 | doi = 10.1016/S0952-7915(98)80031-9 }}</ref>

===C-type carbohydrate recognition domains (CRDs)=== The 8 tandem CRDs in the extracellular region of the mannose receptor share only 30% homology with each other. They each contain at least some of the amino acid residues necessary for Ca2+ and ligand binding, common to functional C-type CRDs. Only CRDs 4 and 5 contain all of the residues required for sugar binding, forming a protease-resistant ligand-binding core. The most common ligand is terminal mannose residues, but ''N''-acetylglucosamine and fucose also bind.<ref name="Stahl1998"/>

The main interaction between CRD-4 and its sugar ligand is through direct ligation to the conserved Ca2+ in the sugar-binding site, in a similar way to the binding mechanism of mannan-binding lectin (MBL). However, a quarter of the free energy of sugar-binding is associated with the hydrophobic stacking interactions formed between one face of the sugar ring and the side chain of a conserved tyrosine residue in the binding site, which is not seen in MBL. Despite the similarities in mannose-binding between the mannose receptor and MBL, these differences suggest that mannose-binding by the mannose receptor evolved separately to that of other C-type lectins.<ref name="Taylor1997">{{cite journal |vauthors=Mullin NP, Hitchen PG, Taylor ME | title = Mechanism of Ca2+ and monosaccharide binding to a C-type carbohydrate-recognition domain of the macrophage mannose receptor | journal = Journal of Biological Chemistry | volume = 272 | issue = 9 | pages = 5668–81 | year = 1997 | pmid = 9038177 | doi = 10.1074/jbc.272.9.5668| doi-access = free }}</ref>

Individually, the CRDs bind mannose with only weak affinity. High affinity binding is thought to result from the clustering of multiple CRDs. This clustering allows for binding of multivalent, branched ligands such as high-mannose N-linked oligosaccharides.<ref name="Drickamer1996">{{cite journal |vauthors=Weis WI, Drickamer K | title = Structural basis of lectin-carbohydrate recognition | journal = Annual Review of Biochemistry | volume = 65 | pages = 441–73 | year = 1996 | pmid = 8811186 | doi = 10.1146/annurev.bi.65.070196.002301 }}</ref>

===Conformation=== It has been suggested that the mannose receptor can exist in at least two different structural conformations. The C-type CRDs are each separated by linker regions of 10-20 amino acids containing a number of proline residues, whose cyclic side chain is fairly rigid and favours a conformation in which the N-terminal cysteine-rich domain is extended as far away from the plasma membrane as possible.<ref name="Llorca2008">{{cite journal | author = Llorca O | title = Extended and bent conformations of the mannose receptor family | journal = Cellular and Molecular Life Sciences | volume = 65 | issue = 9 | pages = 1302–10 | year = 2008 | pmid = 18193159 | doi = 10.1007/s00018-007-7497-9 | s2cid = 5038725 | pmc = 11131820 }}</ref>

Alternatively, interactions between neighbouring CRDs may hold them in close proximity to one another and cause the extracellular region of the receptor to bend, bringing the N-terminal cysteine-rich domain into close contact with the CRDs. This would position CRDs 4 and 5 furthest from the membrane to maximise their interaction with potential ligands. The resistance to proteolysis shown by CRDs 4 and 5 suggests physical interactions between the two domains does occur, thereby supporting the existence of this U-shaped conformation.<ref name="Llorca2008"/>

It is thought that transitions between these two conformations occur in a pH-dependent manner, regulating ligand selectivity and release during endocytosis. The lower, more acidic pH of early endosomes is thought to be responsible for ligand release.<ref name="Llorca2008"/>

===Proteolytic processing=== A functional, soluble form of the mannose receptor is produced upon proteolytic cleavage of the membrane-bound form by metalloproteases found in the extracellular environment.<ref name="Jordens1999">{{cite journal |vauthors=Jordens R, Thompson A, Amons R, Koning F | title = Human dendritic cells shed a functional, soluble form of the mannose receptor | journal = International Immunology | volume = 11 | issue = 11 | pages = 1775–80 | year = 1999 | pmid = 10545481 | doi = 10.1093/intimm/11.11.1775| doi-access = }}</ref><ref name="Martinez1998">{{cite journal |vauthors=Martínez-Pomares L, Mahoney JA, Káposzta R, Linehan SA, Stahl PD, Gordon S | title = A functional soluble form of the murine mannose receptor is produced by macrophages in vitro and is present in mouse serum | journal = Journal of Biological Chemistry | volume = 273 | issue = 36 | pages = 23376–80 | year = 1998 | pmid = 9722572 | doi = 10.1074/jbc.273.36.23376| doi-access = free | hdl = 2437/116851 | hdl-access = free }}</ref>

The soluble protein consists of the entire extracellular region of the receptor and it may be involved in transport of mannosylated proteins away from sites of inflammation.<ref name="Martinez2012"/> Shedding of the mannose receptor from macrophages has been shown to be enhanced upon recognition of fungal pathogens such as ''Candida albicans'' and ''Aspergillus fumigatus'', which suggests the soluble form may play a role in fungal pathogen recognition. In this way, the balance between membrane-bound and soluble mannose receptor could affect targeting of fungal pathogens during the course of infection.<ref name="Gazi2011">{{cite journal |vauthors=Gazi U, Rosas M, Singh S, Heinsbroek S, Haq I, Johnson S, Brown GD, Williams DL, Taylor PR, Martinez-Pomares L | title = Fungal recognition enhances mannose receptor shedding through dectin-1 engagement | journal = Journal of Biological Chemistry | volume = 286 | issue = 10 | pages = 7822–9 | year = 2011 | pmid = 21205820 | pmc = 3048669 | doi = 10.1074/jbc.M110.185025 | doi-access = free }}</ref>

===Glycosylation=== The mannose receptor is heavily glycosylated and its N-linked glycosylation sites are highly conserved between mice and humans, indicating an important role for this post-translational modification. The presence of sialic acid residues on N-linked glycans of the mannose receptor is important for its role in binding both sulphated and mannosylated glycoproteins. Sialylation regulates multimerisation of the receptor, which is known to influence binding to sulphated glycoproteins. Terminal sialic acid residues are also known to be required for binding to mannosylated glycans. The absence of sialic acid reduces the receptors ability to bind and internalise mannosylated glycans, but does not affect its localisation to the plasma membrane or its endocytic activity.<ref name="Martinez2012"/><ref name="Su2005">{{cite journal |vauthors=Su Y, Bakker T, Harris J, Tsang C, Brown GD, Wormald MR, Gordon S, Dwek RA, Rudd PM, Martinez-Pomares L | title = Glycosylation influences the lectin activities of the macrophage mannose receptor | journal = Journal of Biological Chemistry | volume = 280 | issue = 38 | pages = 32811–20 | year = 2005 | pmid = 15983039 | doi = 10.1074/jbc.M503457200 | doi-access = free }}</ref>

==Function==

===Phagocytosis of pathogens=== A number of pathogenic microorganisms, including ''C. albicans'',<ref name="Martinez1998"/><ref name="Marodi1991">{{cite journal |vauthors=Maródi L, Korchak HM, Johnston RB | title = Mechanisms of host defense against ''Candida'' species. I. Phagocytosis by monocytes and monocyte-derived macrophages | journal = Journal of Immunology | volume = 146 | issue = 8 | pages = 2783–9 | year = 1991 | doi = 10.4049/jimmunol.146.8.2783 | pmid = 1901885 | doi-access = free }}</ref> ''Pneumocystis carinii''<ref name="Ezekowitz1991">{{cite journal |vauthors=Ezekowitz RA, Williams DJ, Koziel H, Armstrong MY, Warner A, Richards FF, Rose RM | title = Uptake of ''Pneumocystis carinii'' mediated by the macrophage mannose receptor | journal = Nature | volume = 351 | issue = 6322 | pages = 155–8 | year = 1991 | pmid = 1903183 | doi = 10.1038/351155a0 | bibcode = 1991Natur.351..155E | s2cid = 1763804 }}</ref><ref name="O'Riordan1995">{{cite journal |vauthors=O'Riordan DM, Standing JE, Limper AH | title = ''Pneumocystis carinii'' glycoprotein A binds macrophage mannose receptors | journal = Infection and Immunity | volume = 63 | issue = 3 | pages = 779–84 | year = 1995 | pmid = 7868247 | pmc = 173070 | doi = 10.1128/IAI.63.3.779-784.1995}}</ref> and ''Leishmania donovani''<ref name="Chakraborty1998">{{cite journal |vauthors=Chakraborty R, Chakraborty P, Basu MK | title = Macrophage mannosyl fucosyl receptor: its role in invasion of virulent and avirulent ''L. donovani'' promastigotes | journal = Bioscience Reports | volume = 18 | issue = 3 | pages = 129–42 | year = 1998 | pmid = 9798785 | doi = 10.1023/A:1020192512001| s2cid = 4903749 }}</ref><ref name="Chakraborty2001">{{cite journal |vauthors=Chakraborty P, Ghosh D, Basu MK | title = Modulation of macrophage mannose receptor affects the uptake of virulent and avirulent ''Leishmania donovani'' promastigotes | journal = Journal of Parasitology | volume = 87 | issue = 5 | pages = 1023–7 | year = 2001 | pmid = 11695359 | doi = 10.1645/0022-3395(2001)087[1023:MOMMRA]2.0.CO;2 | s2cid = 26732461 }}</ref> display glycans on their surfaces with terminal mannose residues that are recognised by the C-type CRDs of the mannose receptor, thereby acting as a marker of non-self. Upon recognition, the receptor internalises the bound pathogen and transports it to lysosomes for degradation via the phagocytic pathway. In this way, the mannose receptor acts as a pattern recognition receptor. The presence of a di-aromatic FENTLY (Phe-Glu-Asn-Thr-Leu-Tyr) sequence motif in the cytoplasmic tail of the receptor is vital for its clathrin-mediated internalization.<ref name="Gazi2009"/> This is supported by the evidence that Cos-1 cells transfected with the mannose receptor lacking its C-terminal tail are unable to endocytose ''C. albicans'' and ''P. carinii''.<ref name="Gazi2009"/>

Surprisingly, mannose receptor knockout mice do not show increased susceptibility to infection, which suggests that the receptor is not essential for phagocytosis. However, its involvement cannot be rejected since other mechanisms may compensate. For example, infection of knockout mice with ''P. carinii'' resulted in increased recruitment of macrophages to the site of infection. Furthermore, other receptors present on the surface of phagocytic cells, such as DC-SIGN, SIGNR1 and Endo180, exhibit similar ligand binding ability to the mannose receptor and so it is likely that in its absence, these proteins are able to compensate and induce phagocytosis.<ref name="Gazi2009"/>

The ability of the mannose receptor to aid in pathogen internalisation is also thought to facilitate infection by ''Mycobacterium tuberculosis'' and ''Mycobacterium leprae''. These bacteria reside and multiply in macrophages, preventing formation of the phagolysosome to avoid degradation. Hence, by mediating their entrance into the macrophage, blocking the mannose receptor helps these pathogens to infect and grow in their target cell.<ref name="Gazi2009"/><ref name="Kang2005">{{cite journal |vauthors=Kang PB, Azad AK, Torrelles JB, Kaufman TM, Beharka A, Tibesar E, DesJardin LE, Schlesinger LS | title = The human macrophage mannose receptor directs Mycobacterium tuberculosis lipoarabinomannan-mediated phagosome biogenesis | journal = Journal of Experimental Medicine | volume = 202 | issue = 7 | pages = 987–99 | year = 2005 | pmid = 16203868 | pmc = 2213176 | doi = 10.1084/jem.20051239 }}</ref>

===Clathrin-mediated endocytosis=== The CRD regions of the mannose receptor on liver sinusoidal endothelial cells remove a number of waste material ranging from soluble macromolecules to large particulate matter.<ref name="ReferenceA">{{cite journal |last1=Sørensen |first1=KK |last2=Simon-Santamaria |first2=J |last3=McCuskey |first3=RS |last4=Smedsrød |first4=B |title=Liver Sinusoidal Endothelial Cells. |journal=Comprehensive Physiology |date=20 September 2015 |volume=5 |issue=4 |pages=1751��74 |doi=10.1002/cphy.c140078 |pmid=26426467|doi-access=free }}</ref> These include lysosomal enzymes,<ref>{{cite journal |last1=Elvevold |first1=K |last2=Simon-Santamaria |first2=J |last3=Hasvold |first3=H |last4=McCourt |first4=P |last5=Smedsrød |first5=B |last6=Sørensen |first6=KK |title=Liver sinusoidal endothelial cells depend on mannose receptor-mediated recruitment of lysosomal enzymes for normal degradation capacity. |journal=Hepatology |date=December 2008 |volume=48 |issue=6 |pages=2007–15 |doi=10.1002/hep.22527 |pmid=19026003|s2cid=29069000 |doi-access= }}</ref> collagen α-chains,<ref>{{cite journal |last1=Malovic |first1=I |last2=Sørensen |first2=KK |last3=Elvevold |first3=KH |last4=Nedredal |first4=GI |last5=Paulsen |first5=S |last6=Erofeev |first6=AV |last7=Smedsrød |first7=BH |last8=McCourt |first8=PA |title=The mannose receptor on murine liver sinusoidal endothelial cells is the main denatured collagen clearance receptor. |journal=Hepatology |date=June 2007 |volume=45 |issue=6 |pages=1454–61 |doi=10.1002/hep.21639 |pmid=17518370|s2cid=26022255 |doi-access=free }}</ref> C-terminal propeptides of type I pro-collagens,<ref>{{cite journal |last1=Smedsrød |first1=B |last2=Melkko |first2=J |last3=Risteli |first3=L |last4=Risteli |first4=J |title=Circulating C-terminal propeptide of type I procollagen is cleared mainly via the mannose receptor in liver endothelial cells. |journal=The Biochemical Journal |date=15 October 1990 |volume=271 |issue=2 |pages=345–50 |pmid=2241919|pmc=1149560 |doi=10.1042/bj2710345 }}</ref> and tissue plasminogen activator.<ref>{{cite journal |last1=Smedsrød |first1=B |last2=Einarsson |first2=M |last3=Pertoft |first3=H |title=Tissue plasminogen activator is endocytosed by mannose and galactose receptors of rat liver cells. |journal=Thrombosis and Haemostasis |date=16 June 1988 |volume=59 |issue=3 |pages=480–4 |pmid=2847350|doi=10.1055/s-0038-1647519 |doi-access=free }}</ref> Binding studies indicate that each liver sinusoidal endothelial cell expresses a surface pool of 20,000-25,000 mannose receptors. The mannose receptor on liver sinusoidal endothelial cell is a rapidly recycling receptor, with a Ke (endocytotic rate constant) of 4.12 min-1, which corresponds to a half-life of 10 s for the surface pool of receptor-ligand complexes.<ref>{{cite journal |last1=Magnusson |first1=S |last2=Berg |first2=T |title=Extremely rapid endocytosis mediated by the mannose receptor of sinusoidal endothelial rat liver cells. |journal=The Biochemical Journal |date=1 February 1989 |volume=257 |issue=3 |pages=651–6 |pmid=2930475|pmc=1135637 |doi=10.1042/bj2570651 }}</ref>

As opposed to macrophages that use the mannose receptors for phagocytosis of particulate matter >200 nm, the mannose receptor on liver sinusoidal endothelial cells mediates clathrin-mediated endocytosis of macromolecules and nanoparticles <200 nm.<ref name="ReferenceA"/>

===Antigen presentation=== The mannose receptor may also play a role in antigen uptake and presentation by immature dendritic cells in the adaptive immune system. Upon binding to the receptor, mannosylated antigens are internalised and transported to endocytic compartments within the cell for loading onto major histocompatibility complex (MHC) molecules or other related antigen-presentation molecules. An indirect example of this is the processing of the glycolipid antigen lipoarabinomannan, derived from Mycobacteria. Lipoarabinomannan (LAM) is presented to T cells in complex with CD1b, but is also able to bind to the mannose receptor. Since the presence of mannan, an alternative ligand, inhibits LAM-dependent T cell proliferation, it is suggested that the receptor binds extracellular LAM, internalises it and then transports it to endocytic vesicles to be loaded onto CD1b.<ref name="Stahl1998"/>

Mature dendritic cells and macrophages use the mannose receptor for antigen presentation in a different way. The cleaved, soluble receptor binds to circulating antigens and directs them to effector cells in lymphoid organs via its cysteine-rich domain, thus activating the adaptive immune system.<ref name="Stahl1998"/>

===Intracellular signalling=== The cytoplasmic tail of the mannose receptor does not contain any signalling motifs, yet the receptor has proven to be essential for production of both pro- and anti-inflammatory cytokines, indicating a more passive role for the receptor in phagocytosis of pathogens.<ref name="Gazi2009"/><ref name="Stahl1998"/> This suggests that the mannose receptor is assisted by other cell surface receptors in order to trigger a signalling cascade. For example, it has been shown that HEK 293 cells co-transfected with human mannose receptor and human Toll-like receptor 2 cDNA are able to secrete IL-8 in response to ''P. carinii'' infection, whereas those transfected with either receptor alone did not.<ref name="Tachado2007">{{cite journal |vauthors=Tachado SD, Zhang J, Zhu J, Patel N, Cushion M, Koziel H | title = Pneumocystis-mediated IL-8 release by macrophages requires coexpression of mannose receptors and TLR2 | journal = Journal of Leukocyte Biology | volume = 81 | issue = 1 | pages = 205–11 | year = 2007 | pmid = 17020928 | doi = 10.1189/jlb.1005580 | s2cid = 15056895 | doi-access = }}</ref> It is possible that the two receptors form a complex on the cell surface that facilitates signal transduction upon pathogenic challenge.

===Resolution of inflammation=== Another key role of the mannose receptor is to regulate the levels of molecules released into the circulation during the inflammatory response. In response to pathological events, glycoproteins including lysosomal hydrolases, tissue plasminogen activator and neutrophil myeloperoxidase are released to help fight off any invading microorganisms. Once the threat has subsided, these glycoproteins can be damaging to host tissues so their levels in the circulation must be strictly controlled.<ref name="Gazi2009"/>

High-mannose oligosaccharides present on the surface of these glycoproteins act to mark their transient nature, since they are eventually recognised by the mannose receptor and removed from the circulation. Mannose receptor knockout mice are less able to clear these proteins, and show increased concentrations of a number of lysosomal hydrolases in the blood.<ref name="Lee2002"/>

Consistent with this function, the mannose receptor is expressed at low levels during inflammation and at high levels during the resolution of inflammation, to ensure inflammatory agents are removed from the circulation only at the appropriate time.<ref name="Lee2002"/>

===Clearance of glycoprotein hormones=== The N-terminal cysteine-rich domain of the mannose receptor plays an important role in the recognition of sulphated glycoprotein hormones and their clearance from the circulation.<ref name="Stahl1998"/>

Glycoprotein hormones such as lutropin, which triggers release of the egg during ovulation, must stimulate their receptors in pulses to avoid receptor desensitisation. Glycans on their surface are capped with sulphated ''N''-Acetylgalactosamine (GalNAc), making them ligands for the cysteine-rich ricin homology domain of the mannose receptor. This tag ensures a cycle of release, stimulation, and removal from the circulation.<ref name="IntroToGlycobiology"/>

Knockout mice lacking the enzyme required to add the sulphated GalNAc capping structure show longer half-lives for lutropin, which results in increased receptor activation and oestrogen production. Female knockout mice reach sexual maturity faster than their wild-type counterparts, have a longer oestrus cycle and produce more litters. Thus, the sulphated GalNAc tag is very important in regulating serum concentrations of certain glycoprotein hormones.<ref name="IntroToGlycobiology"/>

==Types==

Humans express two types of mannose receptors, each encoded by its own gene:

{| class="wikitable" |- ! Gene !! Protein !! Alternative names |- | MRC1 || Macrophage mannose receptor 1 || C-type mannose receptor 1, C-type lectin domain family 13 member D (CLEC13D), CD206, MMR |- | MRC2 || Macrophage mannose receptor 2 || C-type mannose receptor 2, Urokinase-type plasminogen activator receptor-associated protein, CD280 |}

==Applications in health and disease== The selective internalisation properties of the mannose receptor indicate a number of potential applications in health and disease. By manipulating the glycosylation of important bioactive proteins to a highly mannosylated state, their serum levels could be tightly regulated and they could be targeted specifically to cells expressing the mannose receptor. There is also potential for use of the mannose receptor as a target for improved macrophage activation and antigen presentation.<ref name="Lee2002" /><ref name="Stahl1998" /><ref name="pmid28365213">{{cite journal | vauthors = Chang CF, Wan J, Li Q, Renfroe SC, Heller NM, Wang J | title = Alternative activation-skewed microglia/macrophages promote hematoma resolution in experimental intracerebral hemorrhage | journal = Neurobiology of Disease | volume = 103 | pages = 54–69 | date = July 2017 | pmid = 28365213 | doi = 10.1016/j.nbd.2017.03.016 | pmc=5540140}}</ref>

MRC2/Endo180<ref>{{cite web | title = WikiGenes: MRC2 - mannose receptor C, type 2 Homo sapiens | url = https://www.wikigenes.org/e/gene/e/9902.html}}</ref> interacts with Basigin/CD147 via its fourth C-type lectin domain to form a molecular epithelial-mesenchymal transition suppressor complex that if disrupted results in the induction of invasive prostate epithelial cell behavior associated with poor prostate cancer survival.<ref name=pmid25381222>{{cite journal | vauthors = Rodriguez-Teja M, Gronau JH, Minamidate A, Darby S, Gaughan L, Robson C, Mauri F, Waxman J, Sturge J | display-authors = 6 | title = Survival Outcome and EMT Suppression Mediated by a Lectin Domain Interaction of Endo180 and CD147 | journal = Molecular Cancer Research | volume = 13 | issue = 3 | pages = 538–47 | date = March 2015 | pmid = 25381222 | doi = 10.1158/1541-7786.MCR-14-0344-T | doi-access = free }}</ref> Increased basement membrane stiffness due to its glycation can also trigger Endo180-dependent invasion of prostate epithelial cells and this bio-mechanical mechanism is associated with poor prostate cancer survival.<ref name=pmid25408555>{{cite journal | vauthors = Rodriguez-Teja M, Gronau JH, Breit C, Zhang YZ, Minamidate A, Caley MP, McCarthy A, Cox TR, Erler JT, Gaughan L, Darby S, Robson C, Mauri F, Waxman J, Sturge J | display-authors = 6 | title = AGE-modified basement membrane cooperates with Endo180 to promote epithelial cell invasiveness and decrease prostate cancer survival | journal = The Journal of Pathology | volume = 235 | issue = 4 | pages = 581–92 | date = March 2015 | pmid = 25408555 | doi = 10.1002/path.4485 | s2cid = 40735796 | url = http://sure.sunderland.ac.uk/id/eprint/6562/1/Rodriguez-Teja_et_al-2015-The_Journal_of_Pathology.pdf }}</ref> It has been suggested that stabilization of the Endo180-CD147 epithelial-mesenchymal transition suppressor complex and targeting of the non-complexed form of Endo180 in invasive cells could have therapeutic benefit in the prevention of cancer progression and metastasis.<ref name=pmid26576691>{{cite journal | vauthors = Sturge J | title = Endo180 at the cutting edge of bone cancer treatment and beyond | journal = The Journal of Pathology | volume = 238 | issue = 4 | pages = 485–8 | date = March 2016 | pmid = 26576691 | doi = 10.1002/path.4673 | pmc=4819699}}</ref>

==References== {{Reflist|35em}}

==External links== * {{MeshName|mannose+receptor}} * [https://web.archive.org/web/20060506044158/http://users.path.ox.ac.uk/~cholt/sgMMR.html Macrophage Mannose Receptor]

Category:C-type lectins