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Siamon Gordon

Publications and source records attributed to Siamon Gordon.

At least 73 records · Page 4Linked to original sources
PubMed2004

Expression of the beta-glucan receptor, Dectin-1, on murine leukocytes in situ correlates with its function in pathogen recognition and reveals potential roles in leukocyte interactions.

Dectin-1 is a pathogen-recognition receptor on macrophages (MPhis), neutrophils, and dendritic cells (DCs). On MPhis and bone marrow-derived DCs, it has been shown to mediate the nonopsonic recognition of and response to soluble and particulate yeast beta-glucans. We have optimized the immunohistochemical detection of Dectin-1 and demonstrated its expression on neutrophils, subpopulations of MPhis in splenic red and white pulp, alveolar MPhis, Kupffer cells, and MPhis and DCs in the lamina propria of gut villi. This is consistent with its role in pathogen surveillance. A significant proportion of CD11c(+) splenic DCs expressed Dectin-1, but expression was not restricted to any one subset. Dectin-1 expression was low on resident MPhis and DCs of skin and was not detected on resident MPhis or DCs in kidney, heart, brain, or eye. The proposed, additional role of Dectin-1 as a coreceptor for T cell activation is supported by its expression on DCs in the T cell areas of the spleen and lymph nodes. Strong expression of Dectin-1 on subpopulations of MPhis and DCs in the medullary and corticomedullary regions of the thymus suggests a role distinct from pathogen recognition. Tissue localization thus revealed potential roles of Dectin-1 in leukocyte interactions during innate immune responses and T cell development.

Age Factors↗
PubMed2004

Development of a specific system for targeting protein to metallophilic macrophages.

The cysteine-rich domain (CR) of the mannose receptor binds sulfated glycoprotein CR ligand (CRL) expressed by subpopulations of myeloid cells in secondary lymphoid organs (CRL(+) cells). In naïve mice, these CRL(+) cells, metallophilic macrophages (M) in spleen and subcapsular sinus M in lymph nodes, are located strategically for antigen capture and are adjacent to B cell follicles, but their role in the immune response is unknown. We have exploited the lectin activity of CR to develop a highly specific system for targeting protein to CRL(+) M. We demonstrate that the sulfated carbohydrates recognized by CR are exposed to the extracellular milieu and mediate highly specific targeting of CR-containing proteins. This model will allow the dissection of the role of metallophilic M in an immune response in vivo.

Animals↗
PubMed2004

Identification and characterization of a novel human myeloid inhibitory C-type lectin-like receptor (MICL) that is predominantly expressed on granulocytes and monocytes.

Inhibitory and activatory C-type lectin-like receptors play an important role in immunity through the regulation of leukocytes. Here, we report the identification and characterization of a novel myeloid inhibitory C-type lectin-like receptor (MICL) whose expression is primarily restricted to granulocytes and monocytes. This receptor, which contains a single C-type lectin-like domain and a cytoplasmic immunoreceptor tyrosine-based inhibitory motif, is related to LOX-1 (lectin-like receptor for oxidized low density lipoprotein-1) and the beta-glucan receptor (Dectin-1) and is variably spliced and highly N-glycosylated. We demonstrate that it preferentially associates with the signaling phosphatases SHP-1 and SHP-2, but not with SHIP. Novel chimeric analyses with a construct combining MICL and the beta-glucan receptor show that MICL can inhibit cellular activation through its cytoplasmic immunoreceptor tyrosine-based inhibitory motif. These data suggest that MICL is a negative regulator of granulocyte and monocyte function.

Alternative Splicing↗
PubMed2004

The role of SIGNR1 and the beta-glucan receptor (dectin-1) in the nonopsonic recognition of yeast by specific macrophages.

We recently demonstrated that the beta-glucan receptor Dectin-1 (betaGR) was the major nonopsonic beta-glucan receptor on macrophages (Mphi) for the yeast-derived particle zymosan. However, on resident peritoneal Mphi, we identified an additional mannan-inhibitable receptor for zymosan that was distinct from the Mphi mannose receptor (MR). In this study, we have studied the mannose-binding potential of murine Mphi and identified the dendritic cell-specific ICAM-3-grabbing nonintegrin homolog, SIGN-related 1 (SIGNR1), as a major MR on murine resident peritoneal Mphi. Both SIGNR1 and betaGR cooperated in the nonopsonic recognition of zymosan by these Mphi. When SIGNR1 was introduced into NIH3T3 fibroblasts or RAW 264.7 Mphi, it conferred marked zymosan-binding potential on these cells. However, in the nonprofessional phagocytes (NIH3T3), SIGNR1 was found to be poorly phagocytic, suggesting that other receptors such as betaGR may play a more dominant role in particle internalization on professional phagocytes. Binding of zymosan to RAW 264.7 Mphi expressing SIGNR1 resulted in TNF-alpha production. Treatment of RAW 264.7 Mphi expressing SIGNR1, which express low levels of betaGR, with beta-glucans had little effect on binding or TNF-alpha production, indicating that there was no absolute requirement for betaGR in this process. These studies have identified SIGNR1 as a major MR for fungal and other pathogens present on specific subsets of Mphi.

Animals↗
PubMed2004

Commentary: C-type lectins on the macrophage cell surface--recent findings.

Interest in the C-type lectin family as a fundamental mediator of diverse immune interactions has grown exponentially in recent years, especially concerning members expressed on NK cells and their roles in anti-viral and anti-tumor immunity. For macrophages, however, collating the roles of the broad range of C-type lectins expressed may be a more complex task. Analysis of the configuration of the C-type lectin(-like) domains among any other conserved modules reveals subfamilies of highly divergent structures. The identified ligands are likewise highly varied; however, most in vivo ligands are unknown and the significance of any recognized interactions is not well understood. In this commentary we review key features of C-type lectin and lectin-like receptor expression on macrophages and discuss recent data that sheds light on their varied functions. We aim to highlight the considerable body of novel/uncharacterized members of this receptor family and to place in context the initial description of CLECSF8, which is reported in this issue of the journal.

Animals↗
PubMed2004

Pathogen recognition or homeostasis? APC receptor functions in innate immunity.

Myeloid cells (macrophages, neutrophils, dendritic cells) express a repertoire of plasma membrane receptors able to recognize all classes of macromolecules. The concept of pattern recognition has emphasized microbial ligands and host defence. However, these receptors play a broader role in tissue homeostasis within multicellular hosts, clearing the extracellular environment of potential undesirable ligands arising endogenously as well as from without. This article will evaluate one of the paradigms that underlie innate immunity.

Animals↗
PubMed2004

The role of scavenger receptors in pathogen recognition and innate immunity.

Scavenger receptors represent a large family of structurally unrelated distinct gene products, expressed by myeloid and selected endothelial cells and able to recognise modified low-density lipoproteins. They also bind and internalise a variety of microbial pathogens, as well as modified or endogenous molecules derived from the host, and contribute to a range of physiological or pathological processes.

Animals↗
PubMed2004

Dectin-1 and its role in the recognition of beta-glucans by macrophages.

beta-Glucans are well known leukocyte activators that have shown protective benefits in a variety of animal disease models, yet the mechanism of action of these carbohydrates remains unknown. We have shown that Dectin-1, a murine type II C-type lectin-like receptor, was able to non-opsonically recognize beta-1,3 and beta-1,6 linked glucan rich particles and intact yeast. Dectin-1 is widely expressed in murine tissues, particularly on the monocyte/macrophage and neutrophil lineages, on dendritic cells (DC) and at a lower level on a sub-population of T cells. The human homologue of Dectin-1 was identified and is functionally similar to the murine molecule. Human Dectin-1 differs from the murine molecule in that it is expressed as two major splice variants that are selectively expressed in particular leukocyte populations. In addition to beta-glucans, Dectin-1 also recognizes an endogenous ligand on T cells. The ligand and the immunological role of Dectin-1 mediated T cell interactions remain to be described.

Animals↗
PubMed2004

Divergent roles for C-type lectins expressed by cells of the innate immune system.

In recent years there has been increasing interest in the diversity and function of carbohydrates present on a range of endogenous mammalian glycoproteins and pathogen surfaces. It is clear that carbohydrate structures are not merely structural components of the molecules which bear them but are, in many instances, a source of information to be decoded by biological systems including the immune system. Macrophages and other antigen presenting cells express a variety of pattern recognition molecules which allow discrimination between self and non-self ligands and are well known for their ability to recognise and internalise foreign antigens. The role of carbohydrates as molecular determinants of self/non-self has been recognised for many years and a family of proteins known as the C-type lectins are implicated as the main players in carbohydrate recognition within the immune system. More recently, C-type lectin receptors which bind ligands other than carbohydrates have been identified, and there are additional receptors which bind both carbohydrate and non-carbohydrate ligands. In this review article we seek to shed light on the varied roles of this family of receptors, particularly those receptors expressed by antigen presenting cells and those with known ligands. We also review more recent data on several members of this family.

Animals↗
PubMed2004

Functional analysis of the murine Emr1 promoter identifies a novel purine-rich regulatory motif required for high-level gene expression in macrophages.

This study has investigated the transcriptional regulation of the Emr1 gene in murine macrophages and defined an enhancer element within the proximal promoter that is necessary for Emr1 expression in myeloid cells. This element consists of an extended purine-rich sequence (PuRS) of 83 consecutive purine residues containing 9 GGAA sequences, the core binding sequence for members of the Ets family of transcription factors. The Ets factor PU.1 associates with this PuRS element both in vitro and in vivo. Using a standard BLAST search we identified similar PuRS elements in other myeloid and nonmyeloid genes. All PuRS elements tested confer enhancer activity onto a heterologous promoter and chromatin immunoprecipitation experiments revealed that PU.1 associates in vivo with the PuRS elements from the genes expressed in myeloid cells. Our results provide evidence that extended purine-rich sequence elements may constitute a new transcription regulatory motif and that PU.1 association is a prerequisite for macrophage-specific expression.

Animals↗
PubMed2004

The potential for Toll-like receptors to collaborate with other innate immune receptors.

Cells of the innate immune system express a large repertoire of germ-line encoded cell-surface glycoprotein receptors including Toll-like receptors (TLRs). TLRs recognize conserved motifs on microbes and induce inflammatory signals. Evidence suggests that individual members of the TLR family or other non-TLR surface antigens either physically or functionally interact with each other and cumulative effects of these interactions instruct the nature and outcome of the immune response to a particular pathogen.

Humans↗
PubMed2004

The role of Dectin-1 in antifungal immunity.

beta-Glucans are structural components of fungal cell walls, which have a stimulatory effect on the immune system. Although a number of receptors for these carbohydrates have been proposed, the recently identified C-type lectin-like receptor, Dectin-1, appears to play a central role. Dectin-1 is expressed on phagocytic cells, including macrophages and neutrophils, and mediates both the internalization and cellular responses to beta-glucan, through unique mechanisms. Dectin-1 can recognize and respond to live fungal pathogens and is being increasingly appreciated as having a key role in the innate responses to these pathogens. In addition to its exogenous ligands, Dectin-1 can recognize an unidentified endogenous ligand on T cells and may act as a co-stimulatory molecule, although its function in these responses is less clear. This review will highlight the current knowledge of Dectin-1 and its potential role in antifungal immunity, as well as deficiencies in our understanding.

Animals↗
PubMed2003

Alveolar macrophage-mediated killing of Pneumocystis carinii f. sp. muris involves molecular recognition by the Dectin-1 beta-glucan receptor.

Innate immune mechanisms against Pneumocystis carinii, a frequent cause of pneumonia in immunocompromised individuals, are not well understood. Using both real time polymerase chain reaction as a measure of organism viability and fluorescent deconvolution microscopy, we show that nonopsonic phagocytosis of P. carinii by alveolar macrophages is mediated by the Dectin-1 beta-glucan receptor and that the subsequent generation of hydrogen peroxide is involved in alveolar macrophage-mediated killing of P. carinii. The macrophage Dectin-1 beta-glucan receptor colocalized with the P. carinii cyst wall. However, blockage of Dectin-1 with high concentrations of anti-Dectin-1 antibody inhibited binding and concomitant killing of P. carinii by alveolar macrophages. Furthermore, RAW 264.7 macrophages overexpressing Dectin-1 bound P. carinii at a higher level than control RAW cells. In the presence of Dectin-1 blockage, killing of opsonized P. carinii could be restored through FcgammaRII/III receptors. Opsonized P. carinii could also be efficiently killed in the presence of FcgammaRII/III receptor blockage through Dectin-1-mediated phagocytosis. We further show that Dectin-1 is required for P. carinii-induced macrophage inflammatory protein 2 production by alveolar macrophages. Taken together, these results show that nonopsonic phagocytosis and subsequent killing of P. carinii by alveolar macrophages is dependent upon recognition by the Dectin-1 beta-glucan receptor.

Animals↗
PubMed2003

The EGF-TM7 family: a postgenomic view.

With the human and mouse genome projects now completed, the receptor repertoire of mammalian cells has finally been elucidated. The EGF-TM7 receptors are a family of class B seven-span transmembrane (TM7) receptors predominantly expressed by cells of the immune system. Within the large TM7 superfamily, the molecular structure and ligand-binding properties of EGF-TM7 receptors are unique. Derived from the processing of a single polypeptide, they are expressed at the cell surface as heterodimers consisting of a large extracellular region associated with a TM7 moiety. Through a variable number of N-terminal epidermal growth factor (EGF)-like domains, EGF-TM7 receptors interact with cellular ligands such as CD55 and chondroitin sulfate. Recent in vivo studies demonstrate a role of the EGF-TM7 receptor CD97 in leukocyte migration. The different number of EGF-TM7 genes in man compared with mice, the chimeric nature of EMR2 and the inactivation of human EMR4 point toward a still-evolving receptor family. Here we discuss the currently available information on this intriguing receptor family.

Amino Acid Sequence↗
PubMed2003

Dectin-1 expression and function are enhanced on alternatively activated and GM-CSF-treated macrophages and are negatively regulated by IL-10, dexamethasone, and lipopolysaccharide.

Dectin-1 is the major macrophage receptor for beta-glucans and generates a proinflammatory response through the recognition of these carbohydrates on fungal pathogens. We have examined the effects of cytokines and other agents on the expression and functions of dectin-1 in both resident and elicited murine peritoneal macrophages (Mphi). Dectin-1 expression was found to be highly up-regulated by GM-CSF and by the cytokines that induce alternative macrophage activation, IL-4 and IL-13. In contrast, IL-10, LPS, and dexamethasone, but not IFN-gamma, down-regulated the expression of this receptor. Modulation of dectin-1 receptor levels correlated with the ability of these macrophages to bind zymosan and significantly affected the contribution of this receptor to the resultant proinflammatory response, as measured by the production of TNF-alpha, although some Mphi-specific differences were observed. These results correlate with the known effects of these cytokines and other agents on the ability of the immune system to recognize and respond to fungal pathogens.

Adjuvants, Immunologic↗
PubMed2003

Proteolytic cleavage of the EMR2 receptor requires both the extracellular stalk and the GPS motif.

EMR2 is a human myeloid-restricted member of the EGF-TM7 receptor family that contains a highly conserved G protein-coupled receptor proteolysis site (GPS) in the membrane-proximal region. Here the post-translational proteolytic cleavage of EMR2 at GPS was investigated. We show the cleavage occurs at Leu517-Ser518 and is independent of the transmembrane domains. The non-covalent association of the resulting extracellular alpha-subunit and transmembrane beta-subunit requires a minimum of eight amino acids in the beta-subunit. The GPS motif is necessary, but not sufficient for receptor cleavage, which requires the entire extracellular stalk. Thus, an alternatively spliced EMR2 isoform with a truncated stalk fails to undergo proteolytic cleavage. Alternative splicing therefore provides a means to regulate GPS cleavage, producing receptors with two distinct structures.

Alternative Splicing↗
PubMed2003

The epidermal growth factor-like domains of the human EMR2 receptor mediate cell attachment through chondroitin sulfate glycosaminoglycans.

Using multivalent protein probes, an evolutionarily conserved endogenous ligand for EMR2, a human myeloid cell-restricted EGF-TM7 receptor, was identified on the surface of a number of adherent cell lines. In addition, in situ staining of the ligand has revealed specific in vivo patterns consistent with a connective tissue distribution. The interaction is conserved across species and mediated exclusively by the largest EMR2 isoform containing 5 epidermal growth factor (EGF)-like modules. Antibody-blocking studies subsequently revealed that the fourth EGF-like module constitutes the major ligand-binding site. The largest isoform of CD97, a related EGF-TM7 molecule containing an identical EGF-like module, also binds to the putative EMR2 ligand. Through the use of mutant Chinese hamster ovary (CHO) cell lines defective in glycosaminoglycans (GAGs) biosynthesis as well as the enzymatic removal of specific cell surface GAGs, the molecular identity of the EMR2 ligand was identified as chondroitin sulfate (CS). Thus, exogenous CS GAGs blocked the EMR2-ligand interaction in a dose-dependent manner. EMR2-CS interaction is Ca2+- and sulphation-dependent and results in cell attachment. This is the first report of a GAG ligand for the TM7 receptors extending the already vast repertoire of stimuli of the GPCR superfamily.

Alternative Splicing↗