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Zymosan stimulation of MyD88-deficient bone marrow-derived macrophages

ABSTRACT: Innate immune pattern recognition receptors play critical roles in pathogen detection and initiation of antimicrobial responses. We and others have previously demonstrated the importance of the beta-glucan receptor Dectin-1 in the recognition of pathogenic fungi by macrophages and dendritic cells, and have elucidated some of the mechanisms by which Dectin-1 signals to coordinate the antifungal response. While Dectin-1 signals alone are sufficient to trigger phagocytosis and Src-Syk-mediated induction of antimicrobial reactive oxygen species, collaboration with Toll-like receptor (TLR)2 signaling enhances NF-kB activation and regulates cytokine production. In this study we demonstrate that Dectin-1 signaling can also directly modulate gene expression via activation of nuclear transcription of activated T cells (NFAT) transcription factors. Dectin-1 ligation by zymosan particles or live Candida albicans yeast triggers NFAT activation in macrophages and dendritic cells. Dectin-1-triggered NFAT activation plays a role in the induction of Egr2 and Egr3 transcription factors, and cyclooxygenase 2 (Cox-2). Furthermore, we show that NFAT activation regulates IL-2, IL-10 and IL-12 p70 production by zymosan-stimulated dendritic cells. These data establish NFAT activation in myeloid cells as a novel mechanism of regulation of the innate antimicrobial response. Keywords: stress response

ORGANISM(S): Mus musculus

PROVIDER: GSE6376 | GEO | 2007/01/30

SECONDARY ACCESSION(S): PRJNA99601

REPOSITORIES: GEO

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Transcription profiling of mouse MyD88-deficient bone marrow-derived macrophages treated with Zymosan

Project description:Innate immune pattern recognition receptors play critical roles in pathogen detection and initiation of antimicrobial responses. We and others have previously demonstrated the importance of the beta-glucan receptor Dectin-1 in the recognition of pathogenic fungi by macrophages and dendritic cells, and have elucidated some of the mechanisms by which Dectin-1 signals to coordinate the antifungal response. While Dectin-1 signals alone are sufficient to trigger phagocytosis and Src-Syk-mediated induction of antimicrobial reactive oxygen species, collaboration with Toll-like receptor (TLR)2 signaling enhances NF-kB activation and regulates cytokine production. In this study we demonstrate that Dectin-1 signaling can also directly modulate gene expression via activation of nuclear transcription of activated T cells (NFAT) transcription factors. Dectin-1 ligation by zymosan particles or live Candida albicans yeast triggers NFAT activation in macrophages and dendritic cells. Dectin-1-triggered NFAT activation plays a role in the induction of Egr2 and Egr3 transcription factors, and cyclooxygenase 2 (Cox-2). Furthermore, we show that NFAT activation regulates IL-2, IL-10 and IL-12 p70 production by zymosan-stimulated dendritic cells. These data establish NFAT activation in myeloid cells as a novel mechanism of regulation of the innate antimicrobial response. Experiment Overall Design: Bone marrow-derived macrophages deficient in MyD88 were stimulated with zymosan, and total RNA was extracted 120 minutes after stimulation for comparison to macrophages grown under the same conditions, but not stimulated.

2008-06-14 | E-GEOD-6376 | biostudies-arrayexpress

Genome wide mapping of NFAT1 binding sites in dendritic cells and of chromatin state in steady and dectin-1 activated dendritic cell line D1

Project description:We generated genome-wide chromatin-state maps of mouse dendritic cells in steady and dectin-1 activated with or without NFAT inhibitor FK506. We found the differential H3K4me3 signatures in these cells. This study provides the epigenetic signatures of steady, dectin-1activated with or without NFAT inhibition. We also generated stable dendritic cell line D1 expressing a V5 tagging NFAT1. This cell line was used to map the global binding sites of NFAT1 upon dectin-1 activation with 10ug/ml curdlan for 30 minutes. examine NFAT1-v5 genome wide binding sites and differential H3K4me3 epigenetic modification in steady, dectinn-1 activated with or without NFAT inhibiton.

2015-01-05 | E-GEOD-59998 | biostudies-arrayexpress

Genome wide mapping of NFAT1 binding sites in dendritic cells and of chromatin state in steady and dectin-1 activated dendritic cell line D1

2015-01-05 | GSE59998 | GEO

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-mediated signaling leads to characteristic gene expressions in rat mast cells

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2015-02-04 | E-GEOD-59896 | biostudies-arrayexpress

Gene expression in dendritic cells stimulated with LPS in conditions allowing or inhibiting NFAT activation

Project description:Interleukin-2 (IL-2) is one of the molecules produced by mouse dendritic cells (DCs) after stimulation by Toll like receptor (TLR) agonists. By analogy with the events following T-cell receptor (TCR) engagement leading to IL-2 production we have observed that DC stimulation with lipopolysaccharide (LPS) induces Src-family kinase and phospholipase C (PLC)Î³2 activation, influx of extracellular Ca2+ and calcineurin-dependent nuclear NFAT translocation. We have also observed that the initiation of this pathway is independent of TLR4 engagement, and dependent exclusively on CD14. To determine the role of NFAT in LPS activated dendritic cells we have performed microarray analysis in conditions allowing or inhibiting NFAT activation. We show here that LPS-induced NFAT activation via CD14 is necessary to cause death of terminally differentiated DCs, an event that is essential for maintaining self-tolerance and preventing autoimmunity. Consequently, blocking this pathway in vivo causes prolonged DC survival and an increase in T cell priming capability. Gene expression analyses were performed using Affymetrix GeneChips in the following groups of murine bone marrow-derived dendritic cells: 1) CD14-deficient BMDCs stimulated with LPS; 2) wtBMDCs stimulated with LPS in presence of EGTA; 3) wtBMDCs stimulated with LPS. This experimental setting allowed us to select for effects due to Ca2+ fluxes and exclude the effects due to other causes, particularly the block of TRIF recruitment in CD14-deficient cells and the EGTA effects unrelated to Ca2+ chelation.

2010-03-04 | E-GEOD-15718 | biostudies-arrayexpress

Gene expression in dendritic cells stimulated with LPS in conditions allowing or inhibiting NFAT activation

2009-06-17 | GSE15718 | GEO

Pathogen size alters C-type lectin receptor signaling in dendritic cells to influence CD4 Th9 cell differentiation

Project description:Dectin-1 recognizes β-glucan in fungal cell walls, and activation of Dectin-1 in dendritic cells (DCs) influences immune responses against fungi. Although many studies have shown that Dectin-1 activated DCs induce different subsets of T helper cells according to different cytokine milieus, the precise mechanisms underlying such differences remain unknown. By harnessing polymorphic Candida albicans and polystyrene beads of different sizes, we found that target size influences production of cytokine that control differentiation of T helper cell subsets. Hyphal C. albicans and large beads activate DCs but cannot be phagocytosed due to their size, which prolongs the duration of Dectin-1 signaling. Transcriptomic analysis revealed that the expression of Il33 was significantly increased by larger targets, and increased IL-33 expression promoted TH9 responses. Expression of IL-33 was regulated by Dectin-1-SYK-PLCγ-CARD9-ERK pathway. Altogether, our study demonstrates that size of fungi can be a determining factor in which DCs induce context-appropriate adaptive immune responses.

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Murine zymosan-induced peritonitis model

Project description:Total RNA was extracted from monocyte and macrophages isolated from the peritoneal cavity of un-inflamed mice or 4, 24, 48 an 72h after mice had been injected with 0.1 or 10mg zymosan

2011-07-30 | E-MEXP-3189 | biostudies-arrayexpress

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