Disease relevance of Clec7a

• A similar requirement for dectin-1 in TNF-alpha production was observed for macrophages infected with M bovis Bacillus Calmette-Guerin (BCG), M phlei, M avium 2151-rough, and M tuberculosis H37Ra [1].
• We conclude that the MR is not required for the normal host defense during disseminated candidiasis or for the phagocytosis of C. albicans and that a beta-glucan receptor may be required for C. albicans phagocytosis [2].

High impact information on Clec7a

• 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 [3].
• Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins [4].
• Our results establish a fundamental function for beta-glucan recognition by dectin-1 in antifungal immunity and demonstrate a signaling non-Toll-like pattern-recognition receptor required for the induction of protective immune responses [5].
• Dectin-1-deficient leukocytes demonstrated significantly impaired responses to fungi even in the presence of opsonins [5].
• Dectin-1 is a C-type lectin involved in the recognition of beta-glucans found in the cell walls of fungi [6].

Biological context of Clec7a

• 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 [7].
• Furthermore, these results identify Dectin-1 as a new target for examining the immunomodulatory properties of beta-glucans for therapeutic drug design [8].
• It is important that blockade of dectin-1 receptor inhibited the phagocytosis of Zy particles by WT and PTX3 Tg macrophages, pointing out the relevant role of dectin-1 as the main receptor involved in Zy uptake [9].
• Innate immunity to the pathogenic fungus Coccidioides posadasii is dependent on Toll-like receptor 2 and Dectin-1 [10].
• Although requiring tyrosine phosphorylation and the cytoplasmic immunoreceptor tyrosine-based activation motif (ITAM)-like motif, uptake mediated by Dectin-1 was different from any previously reported phagocytic receptor and was not dependent on Syk-kinase in macrophages [11].

Anatomical context of Clec7a

• 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 [12].
• 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 [12].
• 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 [7].
• These findings define Dectin-1 as the leukocyte beta-glucan receptor, first described over 50 years ago, and resolves the long-standing controversy regarding the identity of this important molecule [8].
• Dectin-1, which is expressed at low levels on macrophages and high levels on dendritic cells, contains an immunoreceptor tyrosine-based activation motif-like signaling motif that is tyrosine phosphorylated upon activation [13].

Associations of Clec7a with chemical compounds

• In this study we tried to deduce the amino acid residues in dectin 1 responsible for beta-glucan recognition [7].
• Dectin 1 has a carbohydrate recognition domain (CRD) consisting of six cysteine residues that are highly conserved in C-type lectins [7].
• HEK293 cells transfected with mouse dectin 1 cDNA could bind to a gel-forming (1-->3)-beta-d-glucan, schizophyllan (SPG) [7].
• Using fluorescein-activated cell sorter analysis and reverse transcriptase-polymerase chain reaction, we demonstrated that basal level of Toll-like receptor-6 and Zy-induced dectin-1 expression was slightly but consistently higher in macrophages from Tg mice than in macrophages from WT mice [9].
• 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 [14].
• Phagocytosis of beta-glucan particles and subsequent intracellular production of reactive oxygen species were also mediated by Dectin-1 [15].
• PLCgamma2-deficient DCs also exhibit impaired activation of ERK and JNK MAPKs and AP-1 and NFAT transcription factors in response to Dectin-1 stimulation [16].

Physical interactions of Clec7a

• We previously demonstrated that soluble animated beta-1,3-D-glucan (AG) is internalized after binding to a specific beta-glucan receptor on macrophages [17].

Regulatory relationships of Clec7a

• Blocking dectin-1 significantly inhibited the induction of TNF-alpha and IL-12p70 production by SCG [18].
• Blockage of Dectin-1 with antibodies inhibited cytokine production in elicited mouse peritoneal macrophages [10].
• 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 [19].
• In conclusion, IFN-gamma inhibits both the beta-glucan receptor-mediated endocytosis of AG and the fluid-phase endocytosis of NR, probably by inhibiting the formation of large vesicles [17].

Other interactions of Clec7a

• Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2 [13].
• The expression of beta-glucan receptors, such as CR3 and dectin-1, was up-regulated by CY treatment [18].
• PTX3 function as an opsonin for the dectin-1-dependent internalization of zymosan by macrophages [9].
• Dectin-1 expression enhances TLR-mediated activation of nuclear factor kappa B by beta-glucan-containing particles, and in macrophages and dendritic cells dectin-1 and TLRs are synergistic in mediating production of cytokines such as interleukin 12 and tumor necrosis factor alpha [13].
• Finally, HEK293 cells expressing either TLR2/dectin-1 or TLR4/MD2/CD14 did not respond to C. neoformans in the activation of nuclear factor kappa B (NFkappaB) detected by a luciferase assay [20].

Analytical, diagnostic and therapeutic context of Clec7a

• During filamentous growth, no cell separation or subsequent beta-glucan exposure occurs, and the pathogen fails to activate Dectin-1 [21].
• GALT expression of Dectin-1 and toll-like receptor (TLR) 2, but not TLR4, increased following oral administration of glucan [22].
• Under serum-free conditions the beta-glucan receptor of mouse macrophages mediates phagocytosis of beta-1,3-D-glucan-coated microbeads (diameter 2 microns) [23].
• Here we identify Card9 as a key transducer of Dectin-1 signalling [24].

References