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Dectin-1 intracellular domain determines species-specific ligand spectrum by modulating receptor sensitivity [human]

ABSTRACT: C-type lectin receptors (CLRs) are a large family of immunoreceptors that recognizes polysaccharides exposed on pathogens and triggers innate immune responses. However, the ligand spectrums of the whole members have not been fully understood. In this study, we found that seaweed-derived fucan activates cells expressing human Dectin-1 but not mouse Dectin-1. In fucan, low-valency β-glucan appeared to represent this activity, as the ligand activity was eliminated by the treatment of westase, a β-glucanase. Another low-valency β-glucan, laminarin, also acts as an agonist on human Dectin-1 but not for mouse Dectin-1, whereas high-valency β-glucan curdlan activated both human and mouse Dectin-1. Reciprocal mutagenesis analysis revealed that the ligand-binding domain of human Dectin-1 did not determine its unique sensitivity to low-valency β-glucan. Rather, its intracellular domain contributes to render human Dectin-1 reactive to low-valency β-glucan. Within the hDectin-1 intracellular domain, only two amino acids, Glu2 and Pro5, were sufficient to confer sensitivity on mouse Dectin-1. Conversely, the introduction of mouse-type amino acids, Lys2 and Ser5, to human Dectin-1 reduced the reactivity. These results suggest that the intracellular domain, but not the ligand binding domain, of Dectin-1 modulate their functions which determine the ligand spectrum.

ORGANISM(S): Homo sapiens

PROVIDER: GSE98814 | GEO | 2017/08/25

SECONDARY ACCESSION(S): PRJNA386315

REPOSITORIES: GEO

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Dectin-1 intracellular domain determines species-specific ligand spectrum by modulating receptor sensitivity [mouse]

Project description:C-type lectin receptors (CLRs) are a large family of immunoreceptors that recognizes polysaccharides exposed on pathogens and triggers innate immune responses. However, the ligand spectrums of the whole members have not been fully understood. In this study, we found that seaweed-derived fucan activates cells expressing human Dectin-1 but not mouse Dectin-1. In fucan, low-valency β-glucan appeared to represent this activity, as the ligand activity was eliminated by the treatment of westase, a β-glucanase. Another low-valency β-glucan, laminarin, also acts as an agonist on human Dectin-1 but not for mouse Dectin-1, whereas high-valency β-glucan curdlan activated both human and mouse Dectin-1. Reciprocal mutagenesis analysis revealed that the ligand-binding domain of human Dectin-1 did not determine its unique sensitivity to low-valency β-glucan. Rather, its intracellular domain contributes to render human Dectin-1 reactive to low-valency β-glucan. Within the hDectin-1 intracellular domain, only two amino acids, Glu2 and Pro5, were sufficient to confer sensitivity on mouse Dectin-1. Conversely, the introduction of mouse-type amino acids, Lys2 and Ser5, to human Dectin-1 reduced the reactivity. These results suggest that the intracellular domain, but not the ligand binding domain, of Dectin-1 modulate their functions which determine the ligand spectrum.

2017-08-25 | GSE98825 | GEO

Mus musculus

Project description:Dectin-1 intracellular domain determines species-specific ligand spectrum by modulating receptor sensitivity [mouse]

| PRJNA386316 | ENA

Homo sapiens

Project description:Dectin-1 intracellular domain determines species-specific ligand spectrum by modulating receptor sensitivity [human]

| PRJNA386315 | ENA

RNA sequencing of human monocytes stimulated with murine platelets from wild-type or Clec1b-/- mice

Project description:C-type lectin receptors (CLRs) recognize glycans present on the surface of pathogens or self and mediate host defense as well as homeostasis. Dectin-1 is the most well-characterized CLR which recognizes β-glucan on various pathogens and expressed on human myeloid cells. Recently, we screened various tissue-derived primary cells for Dectin-1 binding and found that human Dectin-1 selectively binds to platelets. By establishing anti-platelet monoclonal antibodies that inhibit human Dectin-1 binding, we identified that CLEC-2 is responsible for the interaction with human Dectin-1. CLEC-2 is critical for lymphangiogenesis in early embryonic stage. In this study, we evaluated the influence on CLEC-2 binding in human monocytes which highly expresses human Dectin-1 by RNA sequencing.

2022-12-20 | GSE196049 | GEO

Candida albicans induces monocyte training via epigenetic programming through a dectin 1-dependent pathway

Project description:Non-specific protective effects against reinfection have been described following infection with Candida albicans. Here we show that mice defective in functional T and B lymphocytes were protected against reinfection with C. albicans in a monocyte-dependent manner. C. albicans and beta glucans induced functional programming of monocytes, leading to enhanced cytokine production in vivo and in vitro. The training required the beta glucan receptor dectin 1 and the non-canonical Raf 1 pathway. Monocyte training by beta-glucans was mediated by epigenetic mechanisms through genome-wide changes in histone trimethylation at H3K4. Pathway analysis showed specific induction of epigenetic changes in genes of innate immunity. The functional programming of monocytes, reminiscent of similar properties of NK cells, has been termed M-bM-^@M-^\trained immunityM-bM-^@M-^] and may be employed for the design of improved vaccination strategies. Chromatin-IP at day7 followed by highthroughput sequencing to look at the differences in H3K4me3 and H3K27me3 binding in Monocytes either cultured in RPMI only versus those trained for 24hrs with beta glucan. Additionally expression analysis was performed by doing strandspecific RNAseq also for both unstimulated and beta glucan trained monocytes for correlating the histone modification changes with the expression changes. Biological replicates were generated from independent samples for H3K4me3 and RNAseq. Additional H3K4me3 ChIP-seq assays were performed for day0 untreated, 24hrs control and beta glucan trained monocytes. H3K4me3 ChIP-seq was also performed for Mouse macrophages both saline(control) and low dose Candida treated.

2012-12-21 | E-GEOD-34260 | biostudies-arrayexpress

Dectin-1 ligands produce distinct training phenotypes in human monocytes through differential activation of signaling networks

Project description:Cells of the innate immune system retain memory of prior exposures through a process known as innate immune training. b-glucan, a Dectin-1 ligand purified from the Candida albicans cell wall, has been one of the most widely utilized and well-characterized ligands for inducing innate immune memory. However, many Dectin-1 agonists exist, and it is not known whether all Dectin-1 ligands produce the same phenotype. Using a well-established in vitro model of trained immunity, we compared two commercially available Dectin-1 agonists with the gold standard b-glucan represented in the literature. We found that depleted zymosan, a b-glucan purified from the Saccharomyces cerevisiae cell wall through alkali treatment, produced near identical training effects as C. albicans b-glucan. However, untreated zymosan produced a distinct training effect from b-glucans at both the transcript and cytokine level. Training with zymosan diminished, rather than potentiated, induction of key cytokines such as TNF, IL-12, and IL-6. Zymosan activated NFkB and AP-1 transcription factors more strongly than b-glucans. The addition of the toll-like receptor (TLR) ligand Pam3CSK4 was sufficient to convert the training effect of b-glucans to a phenotype resembling training with zymosan. We conclude that differential activation of TLR signaling pathways determines the phenotype of innate immune training induced by Dectin-1. These findings bring clarity to the specific question of which Dectin-1 agonists produce prototypical training effects and provides broader insight into how signaling networks regulate innate immune training at large.

2024-01-29 | GSE242947 | GEO

Dectin-1 intracellular domain determines species-specific ligand spectrum by modulating receptor sensitivity

Project description:Dectin-1 intracellular domain determines species-specific ligand spectrum by modulating receptor sensitivity

| PRJNA386319 | ENA

Yeast beta-glucan diets alter bone-marrow derived macrophage function

Project description:Fungal beta-glucans are major drivers of trained immunity which increases long-term protection against secondary infections. Heterogeneity in beta-glucan source, structure and solubility alters interaction with the phagocytic receptor Dectin-1 and could impact strategies to improve trained immunity in humans. Using a panel of diverse beta-glucans we describe the ability of a specific yeast-derived whole-glucan particle (WGP) to reprogramme metabolism and thereby drive trained immunity in human monocyte-derived macrophages in-vitro and mice bone-marrow in-vivo. Presentation of pure, non-soluble, non-aggregated WGPs led to the formation of the Dectin-1 phagocytic synapse with subsequent lysosomal mTOR activation, metabolic reprogramming and epigenetic rewiring. Intraperitoneal or oral administration of WGP drove bone-marrow myelopoiesis and improved mature macrophage responses, pointing to therapeutic and food-based strategies to drive immune training. Thus, the investment of a cell in a trained response relies on specific recognition of beta-glucans presented on intact microbial particles through stimulation of the Dectin-1 phagocytic response.

2023-09-21 | GSE235691 | GEO

Expression data from toll-like receptor 9 (TLR9) knockout macrophages stimulated with β-1,3 glucan beads

Project description:Dectin1 controls the recruitment of TLR9 to β-1,3 glucan beads containing phagosomes. We sought to determine whether Dectin-1 also plays a role in controlling TLR9 dependent gene expression.

2015-09-28 | GSE73474 | GEO

Gene expression in bone marrow-derived dendritic cells obtained from wild-type mice or 3BP2 DL/DL mice stimulated with or without curdlan

Project description:C-type lectin dectin-1 is known to recognize beta-glucans such as curdlan and propagate intracellular signaling for activation of NF-kappa B to induce anti-fungal immunity. Recently, we found that adaptor protein 3BP2 is required for the dectin-1-induced activation of NF-kappa B. In this study, we performed microarray analysis to identify genes of which expression is regulated by dectin-1 and 3BP2.

2024-11-15 | GSE263167 | GEO

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