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PubMed2002

The beta-glucan receptor, dectin-1, is predominantly expressed on the surface of cells of the monocyte/macrophage and neutrophil lineages.

We recently identified dectin-1 (betaGR) as a major beta-glucan receptor on leukocytes and demonstrated that it played a significant role in the non-opsonic recognition of soluble and particulate beta-glucans. Using a novel mAb (2A11) raised against betaGR, we show here that the receptor is not dendritic cell-restricted as first reported, but is broadly expressed, with highest surface expression on populations of myeloid cells (monocyte/macrophage (Mphi) and neutrophil lineages). Dendritic cells and a subpopulation of T cells also expressed the betaGR, but at lower levels. Alveolar Mphi, like inflammatory Mphi, exhibited the highest surface expression of betaGR, indicative of a role for this receptor in immune surveillance. In contrast, resident peritoneal Mphi expressed much lower levels of betaGR on the cell surface. Characterization of the nonopsonic recognition of zymosan by resident peritoneal Mphi suggested the existence of an additional beta-glucan-independent mechanism of zymosan binding that was not observed on elicited or bone marrow-derived Mphi. Although this recognition could be inhibited by mannan, we were able to exclude involvement of the Mphi mannose receptor and complement receptor 3 in this process. These observations imply the existence of an additional mannan-dependent receptor involved in the recognition of zymosan by resident peritoneal Mphi.

3T3 Cells↗

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↗

PubMed2001

A novel cluster of lectin-like receptor genes expressed in monocytic, dendritic and endothelial cells maps close to the NK receptor genes in the human NK gene complex.

The NK gene complex is a region on human chromosome 12 containing several families of lectin-like genes including the CD94 and NKG2 NK receptor genes. We report here that the region telomeric of CD94 contains in addition to the LOX-1 gene the novel human DECTIN-1 and the CLEC-1 and CLEC-2 genes within about 100 kb. Sequence similarities and chromosomal arrangement suggest that these genes form a separate subfamily of lectin-like genes within the NK gene complex. DECTIN-1 is selectively expressed in dendritic cells and to a lower extent in monocytes and macrophages. mRNA forms with and without a stalk exon are observed. During functional maturation of dendritic cells the level of DECTIN-1 mRNA is down-regulated several-fold. CLEC-1 is found to be not only expressed in dendritic cells, but also in endothelial cells and in the latter aspect resembles the LOX-1 gene. Whereas recombinant full-length DECTIN-1 and LOX-1 are transported to the cell surface, CLEC-1 proteins accumulate in perinuclear compartments. We propose that this family of lectin-like genes encodes receptors with important immune and/or scavenger functions in monocytic, dendritic and endothelial cells.

Amino Acid Sequence↗

PubMed2005

Regulated recruitment of DC-SIGN to cell-cell contact regions during zymosan-induced human dendritic cell aggregation.

Zymosan is a beta-glucan, mannan-rich yeast particle widely used to activate the inflammatory response of immune cells. We studied the zymosan-binding potential of human dendritic cells (hDCs) by using specific carbohydrate inhibitors and blocking monoclonal antibodies. We show that DC-specific intercellular adhesion molecule-grabbing nonintegrin (DC-SIGN) is a major nonopsonic recognition receptor for zymosan on hDCs. Indeed, blocking of DC-SIGN inhibited the inflammatory response of DCs to zymosan. We compared the zymosan-binding capacity of hDC-SIGN to that of Dectin-1 and complement receptor 3 (CR3), which are receptors involved in the nonopsonic recognition of these yeast-derived particles. Dectin-1- and DC-SIGN-K562 cells bound to zymosan particles, whereas CR3-K562 cells did not. DC-SIGN and Dectin-1 were also expressed in COS cells to compare their ability to trigger particle internalization in a nonphagocytic cell line. DC-SIGN transfectants were unable to internalize bound particles, indicating that DC-SIGN is primarily involved in recognition but not in particle internalization. Zymosan induced a rapid DC aggregation that was accompanied by a dramatic change of DC-SIGN distribution in the plasma membrane. Under resting conditions, DC-SIGN was diffusely distributed through the cell surface, displaying clusters at the free leading edge. Upon zymosan treatment, DC-SIGN was markedly redistributed to cell-cell contacts, supporting an adhesion role in DC-DC interactions. The mechanism(s) supporting DC-SIGN-mediated intercellular adhesion were further investigated by using DC-SIGN-K562 aggregation. DC-SIGN was highly concentrated at points of cell-cell contact, suggesting a role for enhanced avidity during DC-SIGN-mediated intercellular adhesion.

Animals↗

PubMed2000

Cloning of a second dendritic cell-associated C-type lectin (dectin-2) and its alternatively spliced isoforms.

Using a subtractive cDNA cloning strategy, we isolated previously five novel genes that were expressed abundantly by the murine dendritic cell (DC) line XS52, but not by the J774 macrophage line. One of these genes encoded a unique, DC-associated C-type lectin, termed "dectin-1." Here we report the characterization of a second novel gene that was also expressed in a DC-specific manner. Clone 1B12 encoded a type II membrane-integrated polypeptide of 209 amino acids containing a single carbohydrate recognition domain motif in the COOH terminus. The expression pattern of this molecule, termed "dectin-2," was almost indistinguishable from that for dectin-1; that is, both were expressed abundantly at mRNA and protein levels by the XS52 DC line, but not by non-DC lines, and both were detected in spleen and thymus, as well as in skin resident DC (i.e. Langerhans cells). Interestingly, reverse transcriptase-polymerase chain reaction and immunoblotting revealed multiple bands of dectin-2 transcripts and proteins suggesting molecular heterogeneity. In fact, we isolated additional cDNA clones encoding two distinct, truncated dectin-2 isoforms. Genomic analyses indicated that a full-length dectin-2 (alpha isoform) is encoded by 6 exons, whereas truncated isoforms (beta and gamma) are produced by alternative splicing. We propose that dectin-2 and its isoforms, together with dectin-1, represent a unique subfamily of DC-associated C-type lectins.

Alternative Splicing↗

PubMed2003

Productive infection of dendritic cells by simian immunodeficiency virus in macaque intestinal tissues.

Dendritic cells (DCs) are potent antigen-presenting cells that likely play multiple roles in human immunodeficiency virus-1 (HIV-1) and simian immunodeficiency virus (SIV) pathogenesis. This paper describes the effects of pathogenic SIV infection on the networks of DCs in rhesus macaque (Macaca mulatta) intestinal tissues. Intestinal tissues were obtained from macaques at different stages of disease following infection with the pathogenic SIV/DeltaB670 isolate. The patterns and levels of expression of SIV and DC-associated mRNAs were examined and quantitated directly in intestinal tissue sections. In situ hybridization was performed for SIV, DC-specific ICAM3-grabbing non-integrin (DC-SIGN), DC-specific lysosome-associated membrane glycoprotein (DC-LAMP), DC-specific C-type lectin 1 (DECTIN-1), CC chemokine receptor 6 (CCR6), CCR7, and macrophage inflammatory protein 3alpha (MIP-3alpha/CCL20) mRNAs and quantitative image analysis was performed to measure mRNA expression levels. To identify the cell types productively infected by SIV, simultaneous in situ hybridization and immunohistochemical staining were performed. The DC networks in macaque intestinal tissues were found to be extensive and although they generally remained intact during the course of SIV infection, there were alterations in the expression of markers for immature DCs. One alteration was an increase in the expression in intestinal submucosa of DC-SIGN, a molecule that binds to HIV-1/SIV and increases its infectivity. Concomitant with this increase, it was found that during AIDS, the population of productively infected cells included DCs, based on co-expression of DC-SIGN and DECTIN-1 mRNAs. These data indicate that SIV infection affects subpopulations of macaque intestinal DCs, including productive infection of DC-SIGN+ DCs, the consequences of which are likely to be ongoing viral propagation and decreased immunostimulatory function.

Acquired Immunodeficiency Syndrome↗

PubMed2003

Pattern recognition receptors and differentiation antigens define murine myeloid cell heterogeneity ex vivo.

Recruitment of myeloid cells during inflammatory reactions plays an important role in the propagation and resolution of inflammation. However, the identification and characterization of these cells in mice has been hampered by cellular heterogeneity at the functional and phenotypic level. We have defined criteria for the rapid flow-cytometric identification of monocytes (M(o)), macrophages (MPhi), neutrophils (N(eu)) and eosinophils (E(os)) in murine tissues using novel and established myeloid markers. These criteria were applied to the study of naive mice and mice with experimentally induced inflammation, both local and systemic, and also to a murine model of tumor progression. We show that the murine 7/4 antigen and the beta-glucan receptor, Dectin-1, are particularly useful for the sub-division of myeloid cells into individual populations, even when inflammatory conditions modulate their surface expression. Furthermore, 7/4 expression allows distinction between M(o) recently recruited to a site and the resident cells already present. These studies highlight the heterogeneity of the murine M(o)/MPhi-lineage, define an extended phenotype for murine myeloid cells and greatly facilitate the ex vivo characterization of these cells during very different models of inflammation.

Animals↗

PubMed2001

Immune recognition. A new receptor for beta-glucans.

The carbohydrate polymers known as beta-1,3-d-glucans exert potent effects on the immune system - stimulating antitumour and antimicrobial activity, for example - by binding to receptors on macrophages and other white blood cells and activating them. Although beta-glucans are known to bind to receptors, such as complement receptor 3 (ref. 1), there is evidence that another beta-glucan receptor is present on macrophages. Here we identify this unknown receptor as dectin-1 (ref. 2), a finding that provides new insights into the innate immune recognition of beta-glucans.

3T3 Cells↗

PubMed2004

Characterization of beta-glucan recognition site on C-type lectin, dectin 1.

Dectin 1 is a mammalian cell surface receptor for (1-->3)-beta-d-glucans. Since (1-->3)-beta-d-glucans are commonly present on fungal cell walls, it has been suggested that dectin 1 is important for recognizing fungal invasion. In this study we tried to deduce the amino acid residues in dectin 1 responsible for beta-glucan recognition. HEK293 cells transfected with mouse dectin 1 cDNA could bind to a gel-forming (1-->3)-beta-d-glucan, schizophyllan (SPG). The binding of SPG to a dectin 1 transfectant was inhibited by pretreatment with other beta-glucans having a (1-->3)-beta-d-glucosyl linkage but not by pretreatment with alpha-glucans. Dectin 1 has a carbohydrate recognition domain (CRD) consisting of six cysteine residues that are highly conserved in C-type lectins. We prepared 32 point mutants with mutations in the CRD and analyzed their binding to SPG. Mutations at Trp(221) and His(223) resulted in decreased binding to beta-glucan. Monoclonal antibody 4B2, a dectin- 1 monoclonal antibody which had a blocking effect on the beta-glucan interaction, completely failed to bind the dectin-1 mutant W221A. A mutant with mutations in Trp(221) and His(223) did not have a collaborative effect on Toll-like receptor 2-mediated cellular activation in response to zymosan. These amino acid residues are distinct from residues in other sugar-recognizing peptide sequences of typical C-type lectins. These results suggest that the amino acid sequence W221-I222-H223 is critical for formation of a beta-glucan binding site in the CRD of dectin 1.

Amino Acid Sequence↗

PubMed2002

Simian immunodeficiency virus dramatically alters expression of homeostatic chemokines and dendritic cell markers during infection in vivo.

Dendritic cells (DCs) are potent antigen-presenting cells that likely play multiple roles in human immunodeficiency virus type 1 (HIV-1) pathogenesis. We used the simian immunodeficiency virus (SIV)/macaque model to study the effects of infection on homeostatic chemokine expression and DC localization directly in secondary lymphoid tissues. SIV infection altered the expression of chemokines (CCL19/MIP-3beta, CCL21/ 6Ckine, and CCL20/MIP-3alpha) and of chemokine receptors (CCR7 and CCR6) that drive DC trafficking. CCL19/MIP-3beta, CCL20/MIP-3alpha, CCR6, and CCR7 expression increased in lymph nodes during the early systemic burst of viral replication (acute infection), whereas CCL21/6Ckine expression progressively decreased throughout disease to AIDS. Parallel with the SIV-induced perturbations in chemokine expression were changes in the expression of the DC-associated markers, DC-SIGN, DC-LAMP, and DECTIN-1. During AIDS, DC-LAMP mRNA expression levels were significantly reduced in lymph nodes and spleen, and DC-SIGN levels were significantly reduced in spleen. These findings suggest that the disruption of homeostatic chemokine expression is responsible, in part, for alterations in the networks of antigen-presenting cells in lymphoid tissues, ultimately contributing to systemic immunodeficiency.

Animals↗

PubMed2004

Candida albicans and Saccharomyces cerevisiae induce interleukin-8 production from intestinal epithelial-like Caco-2 cells in the presence of butyric acid.

Intestinal epithelial cells (IEC) are important in initiation and regulation of immune responses against numerous foreign substances including food, microorganisms and their metabolites in the intestine. Since the responses of IEC against yeasts have not yet been well understood, we investigated the effects of Candida albicans, Saccharomyces cerevisiae, and their cell wall components on interleukin-8 (IL-8) secretion by the IEC-like Caco-2 cells. Live cells of both yeast species stimulated Caco-2 cells to produce IL-8 only in the presence of butyric acid, which is a metabolite produced by intestinal bacteria. S. cerevisiae zymosan and glucan also enhanced IL-8 secretion. Treatment of Caco-2 cells with butyric acid increased the expression of mRNAs coding for Toll-like receptor 1 (TLR1), TLR6 and dectin-1, which recognize zymosan. C. albicans induced more IL-8 secretion and also decreased transepithelial electrical resistance more rapidly than S. cerevisiae. These results suggest that both yeasts in the intestine stimulate the host's mucosal immune systems by interacting with IEC.

Butyric Acid↗

PubMed2004

Stimulus-specific defect in the phagocytic pathways of annexin 1 null macrophages.

The role of the glucocorticoid-regulated protein annexin 1 during the process of phagocytosis has been studied using annexin 1 null peritoneal macrophages. Wild type and annexin 1 null macrophages were incubated with several distinct phagocytic targets. No differences were observed in rate or the maximal response with respect to IgG complexes or opsonised zymosan phagocytosis, as assessed by monitoring the production of reactive oxygen species. When annexin 1 null macrophages were incubated with non-opsonised zymosan particles, they exhibited impaired generation of reactive oxygen species, which was linked to a defect in binding of cells to the particles, as determined with fluorescent zymosan. This phenomenon was further confirmed by electron microscopy analysis, where annexin 1 null macrophages internalised fewer non-opsonised zymosan particles. Specific alterations in macrophage plasma membrane markers were observed in the annexin 1 null cells. Whereas no differences in dectin-1 and FcgammaR II/III expression were measured between the two genotypes, decreased membrane CD11b and F4/80 levels were measured selectively in macrophages lacking annexin 1. These cells also responded with an enhanced release of PGE(2) and COX-2 protein expression following addition of the soluble stimulants, LPS and heat-activated IgG. In conclusion, these results suggest that participation of endogenous annexin 1 during zymosan phagocytosis is critical and that this protein plays a tonic inhibitory role during macrophage activation.

Animals↗

PubMed2001

Characterization of the human beta -glucan receptor and its alternatively spliced isoforms.

beta-1,3-d-Glucans are biological response modifiers with potent effects on the immune system. A number of receptors are thought to play a role in mediating these responses, including murine Dectin-1, which we recently identified as a beta-glucan receptor. In this study we describe the characterization of the human homologue of this receptor and show that it is structurally and functionally similar to the mouse receptor. The human beta-glucan receptor is a type II transmembrane receptor with a single extracellular carbohydrate recognition domain and an immunoreceptor tyrosine activation motif in its cytoplasmic tail. The human beta-glucan receptor is widely expressed and functions as a pattern recognition receptor, recognizing a variety of beta-1,3- and/or beta-1,6-linked glucans as well as intact yeast. In contrast to the murine receptor, the human receptor mRNA is alternatively spliced, resulting in two major (A and B) and six minor isoforms. The two major isoforms differ by the presence of a stalk region separating the carbohydrate recognition domain from the transmembrane region and are the only isoforms that are functional for beta-glucan binding. The human receptor also binds T-lymphocytes at a site distinct from the beta-glucan binding site, indicating that this receptor can recognize both endogenous and exogenous ligands.

Alternative Splicing↗

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

Bioaerosols and innate immune responses in airway diseases.

PURPOSE OF REVIEW: We review the role of bioaerosols in the pathogenesis of inflammatory airway disease. The focus is on recent discoveries in innate immune responses induced by common components of bioaerosols. RECENT FINDINGS: Common components of bioaerosols include endotoxin, peptidoglycan and beta-glucan; all of which have been associated with inflammatory airway disease. Endotoxin signaling through toll-like receptor 4 is well characterized and updated. Peptidoglycan is now known to signal through three types of molecules: toll-like receptor 2; peptidoglycan recognition proteins; and nucleotide-binding oligomerization domain molecules. Beta-glucan, a common fungal cell wall component, signals through the newly discovered receptor, dectin-1. Emerging data indicate that genetic polymorphisms influence the response to bioaerosols. SUMMARY: Activation of the innate immune system by bioaerosols is becoming better understood. This knowledge provides an opportunity to better prevent and treat airway diseases that result from environmental exposure.

Aerosols↗

PubMed2003

Nontypeable Haemophilus influenzae activates human eosinophils through beta-glucan receptors.

Eosinophils are a characteristic component of the inflammatory response seen in several diseases, including allergic asthma and chronic obstructive pulmonary disease. After activation, eosinophil-derived products may exert proinflammatory effects and cause considerable tissue damage. In the present study, we investigated innate interactions between the respiratory tract pathogen nontypeable Haemophilus influenzae (NTHi) and human eosinophils. Bacterial binding to eosinophils was dependent on (1-3)-beta-D-glucan receptors, as deduced from blocking experiments using the soluble glucan derivatives laminarin and scleroglucan. In addition, expression of the beta-glucan receptor dectin-1 was shown in eosinophils by reverse transcriptase-polymerase chain reaction. Activation of the beta-glucan receptors by bacteria elicited a time- and dose-dependent respiratory burst in eosinophils. NTHi caused increased expression of the proinflammatory chemokine interleukin-8 as measured by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. Incubation of eosinophils in the presence of NTHi for 4.5 h revealed upregulation of 245 different genes as detected by microarray. Signal transduction-related transcripts were most strongly upregulated, followed by cytokine mRNAs. Our findings suggest that NTHi can induce an innate inflammatory response in eosinophils that is mainly mediated via beta-glucan receptors. This points to possible pathophysiologic mechanisms involving innate recognition of NTHi by eosinophils during infection of the airways, thus promoting inflammation in chronic pulmonary disease.

Eosinophils↗

PubMed2004

CD63 tetraspanin slows down cell migration and translocates to the endosomal-lysosomal-MIICs route after extracellular stimuli in human immature dendritic cells.

We analyzed herein whether members of the tetraspanin superfamily are involved in human immature dendritic cell (DC) functions such as foreign antigen internalization, phagocytosis, and cell migration. We show that CD63, CD9, CD81, CD82, and CD151 are present in immature DCs. Whereas CD9 and CD81 are mostly expressed at the cell surface, CD63 and CD82 are also located in intracellular organelles. Complexes of monoclonal antibody (Mab) FC-5.01-CD63 or Fab-5.01-CD63 were rapidly translocated "outside-in" and followed the endocytic pathway through early endosomes and lysosomes, reaching major histocompatibility complex (MHC) class II-enriched compartments (MIICs) in less than one hour. Internalization of CD63 was also observed during Saccharomyces cerevisiae phagocytosis. Moreover, an association of CD63 with the beta-glycan receptor dectin-1 was observed. Mabs against CD9, CD63, CD81, and CD82 enhanced by 50% the migration induced by the chemokines macrophage inflammatory protein-5 (MIP-5) and MIP-1alpha. Concomitantly, Mabs against CD63 and CD82 diminished the surface expression of CD29, CD11b, CD18, and alpha5 integrins. By immunoprecipitation experiments we found that CD63 associated with integrins CD11b and CD18. These results suggest that CD9, CD63, CD81, and CD82 could play a role in modulating the interactions between immature DCs and their environment, slowing their migratory ability. However, only CD63 would intervene in the internalization of complex antigens.

Antigens, CD↗

PubMed2003

Toll-like receptors: networking for success.

The innate immune system is essential for host defense and is responsible for early detection of potentially pathogenic microorganisms. Upon recognition of microbes by innate immune cells such as macrophages and dendritic cells, diverse signaling pathways are activated that combine to define inflammatory responses that direct sterilization of the threat and/or orchestrate development of the adaptive immune response. Innate immune signaling must be carefully controlled, and regulation comes in part from interactions between activating and inhibiting signaling receptors. Toll-like receptors (TLR) have recently emerged as key receptors responsible for recognizing specific conserved components of microbes including lipopolysaccharides from Gram-negative bacteria, CpG DNA, and flagellin. Full activation of inflammatory responses by TLR may require the assembly of receptor signaling complexes including other transmembrane proteins that may influence signal transduction. In addition to TLR, many additional receptors participate in innate recognition of microbes, and recent studies demonstrate strong interactions between signaling through these receptors and signaling through TLR. Useful models for these interacting signaling pathways are now emerging and should pave the way for understanding the molecular mechanisms that drive the rich diversity of inflammatory responses.

Carrier Proteins↗