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Gene expression of murine DCs from bone marrow and spleen

ABSTRACT: Next to driving hematopoiesis, the bone marrow (BM) also serves as a secondary lymphoid organ, as it can drive T cell priming by resident dendritic cells (DC). When analyzing these DCs in murine BM, we uncovered that they are localized around sinusoids, can (cross)-present antigens, become activated upon intravenous LPS-injection, and for the majority belong to the cDC2 subtype which is associated with Th2/Th17 immunity. Gene-expression profiling revealed that BM-resident DCs are enriched for several c-type lectins, including Dectin-1, which can bind beta-glucans expressed on fungi and yeast. Indeed, DCs in BM were much more efficient in phagocytosis of both yeast-derived zymosan-particles and Aspergillus than their splenic counterparts, which was highly dependent on Dectin-1. DCs in human BM could also phagocytose zymosan, which was dependent on β1-integrins. Moreover, zymosan-stimulated BM-resident DCs enhanced the differentiation of hematopoietic stem and progenitor cells towards neutrophils, while also boosting the maintenance of these progenitors. Our findings signify an important role for BM DCs as translators between infection and hematopoiesis, in particular in anti-fungal immunity. The ability of BM-resident DCs to boost granulopoiesis is relevant from a clinical perspective, and contributes to our understanding of the increased susceptibility for fungal infections following BM damage.

ORGANISM(S): Mus musculus

PROVIDER: GSE182984 | GEO | 2021/08/31

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

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.

2022-04-01 | GSE181734 | GEO

Zymosan stimulation of MyD88-deficient bone marrow-derived macrophages

2007-01-30 | GSE6376 | 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

Stimulation of dendritic cells with cell wall components

Project description:In order to dissect the response from different fungal cell wall components, monocyte-derived dendritic cells obtained from healthy donors were collected and either left untreated, or treated for four hours with either mannan, zymosan, curdlan, whole yeast, or yeast spores. This experiment is related to E-MTAB-1213.

2012-08-28 | E-MTAB-750 | biostudies-arrayexpress

Effect of purification of galactooligosaccharides derived from lactulose with Saccharomyces cerevisiae on their capacity to bind immune cell receptor Dectin-2

Project description:Lactulose-derived oligosaccharides (OsLu) are prebiotic galactooligosaccharides (GOS) known to be beneficial for human health. Many of these carbohydrates are reported to have immunomodulatory properties; however the molecular mechanism is unclear. OsLu produced by enzymatic synthesis can be purified with Saccharomyces cerevisiae (OsLu-Sc). We show that this purification method introduces yeast-derived proteins reactive to Dectin-2, an innate immune receptor for fungal polysaccharides. Using a cell-based bioassay, we tested the binding of OsLu and GOS samples to Dectin-2. While OsLu purified with active charcoal and commercial GOS failed to bind to Dectin-2, we found OsLu-Sc bound to this receptor. The carbohydrate-binding incompetent mutant of Dectin-2 failed to bind to OsLu-Sc. These data suggest that OsLu-Sc introduced carbohydrate ligands for Dectin-2. In accordance with this, proteomic analysis revealed OsLu-Sc contained S. cerevisiae-derived mannoproteins. Therefore, our data highlights the importance of the purification method for OsLu, which may positively affect the bioactivity of OsLu.

2018-12-11 | PXD010495 | Pride

Transcriptional profiles of macrophages in resolving inflammation

Project description:We have performed a comprehensive transcriptional analysis of specific monocyte and macrophage (MM-CM-^X) subsets during an acute self-resolving inflammatory insult. Following initial induction of acute inflammation, tissue resident (Resident) MM-CM-^X are rapidly M-bM-^@M-^XclearedM-bM-^@M-^Y from the inflammatory foci, only becoming recoverable as inflammation resolves. Monocytes are recruited to the inflammatory lesion where they differentiate into MM-CM-^X. We term these monocyte-derived MM-CM-^X M-bM-^@M-^Xinflammation-associatedM-bM-^@M-^Y to distinguish them from Resident MM-CM-^X which are present throughout the inflammatory response and can renew during the resolution of inflammation by proliferation. Comparative analysis of the Mo and MM-CM-^X populations (both M-bM-^@M-^Xinflammation-associatedM-bM-^@M-^Y and Resident MM-CM-^X) identifies select genes expressed in subsets of M-bM-^@M-^Xinflammation-associatedM-bM-^@M-^Y and Resident MM-CM-^X that play important roles in the resolution of inflammation and/or for immunity, including molecules involved in antigen presentation, cell cycle and others associated with M-bM-^@M-^XimmaturityM-bM-^@M-^Y and MM-CM-^X activation. We purified monocyte and macrophage populations from the peritoneal cavity of C57BL/6 mice 4, 18, 72 and 168 hours after the induction of inflammation with intraperitoneal administration of zymosan (2x10^7 particles). We also purified tissue resident macrophages and Ly-6B+ bone marrow monocytes from naive mice as reference populations.

2014-05-09 | E-GEOD-28621 | biostudies-arrayexpress

Genome-wide analysis of the CARD9/Dectin-1 transcriptional program in neutrophils and macrophages by RNA-seq

Project description:Purpose: To characterize Card9-dependent and Card9-independent Dectin-1 mediated gene expression changes in neutrophils and to compare response to Dectin-1 stimulation in neutrophils and macrophages. Method: BM neutrophils from WT and Card9-/- mice were isolated by MACS column purification and treated with or without the Dectin-1 agonist, curdlan for 3 hrs. WT BM-derived macrophages were also treated with or without curdlan for 3hrs before sample collection. Results: We identified both Card9-dependent and Card9-independent gene expression changes with Dectin-1 stimulation in neutrophils. We also identified cell-type specific differences in the response to Dectin-1 stimulation in neutrophils and macrophages. Conclusions: Dectin-1 stimulation induces significant gene expression changes regulated by either canonical Card9-dependent or non-canonical Card9-independent mechanisms.

2021-02-26 | GSE148850 | GEO

The protective effect of inflammatory monocytes during systemic C. albicans infection is dependent on collaboration between C-type lectin-like receptors

Project description:Invasive candidiasis, mainly caused by Candida albicans, is a serious healthcare problem with high mortality rates, particularly in immunocompromised patients. Innate immune cells express pathogen recognition receptors (PRRs) including C-type lectin-like receptors (CLRs) that bind C. albicans to initiate an immune response. Multiple CLRs including Dectin-1, Dectin-2 and Mincle have been proposed individually to contribute to the immune response to C. albicans. However how these receptors collaborate to clear a fungal infection is unknown. Herein, we used novel multi-CLR knockout (KO) mice to decipher the individual, collaborative and collective roles of Dectin-1, Dectin-2 and Mincle during systemic C. albicans infection. These studies revealed an unappreciated and profound role for CLR co-operation in anti-fungal immunity. The protective effect of multiple CLRs was markedly greater than any single receptor, and was mediated through inflammatory monocytes via recognition and phagocytosis of C. albicans, and production of C. albicans-induced cytokines and chemokines. These CLRs were dispensable for mediating similar responses from neutrophils, likely due to lower expression of these CLRs on neutrophils compared to inflammatory monocytes. Concurrent deletion of Dectin-1 and Dectin-2, or all three CLRs, resulted in dramatically increased susceptibility to systemic C. albicans infection compared to mice lacking a single CLR. Multi-CLR KO mice were unable to control fungal growth due to an inadequate early inflammatory monocyte-mediated response. In response to excessive fungal growth, the multi-CLR KO mice mounted a hyper-inflammatory response, likely leading to multiple organ failure. Thus, these data reveal a critical role for CLR co-operation in the effective control of C. albicans and maintenance of organ function during infection.

2019-06-20 | E-MTAB-8030 | biostudies-arrayexpress

Human mesenchymal stem cells

Project description:The identity of cells that establish the hematopoietic microenvironment (HME) in human bone marrow (BM), and of skeletal ("mesenchymal") stem cells (SSCs) found in BM stroma, have long remained elusive. We show that MCAM/CD146-expressing, subendothelial cells in human BM stroma are both the self-renewing SSCs and the cells that transfer the HME at heterotopic sites upon transplantation. Establishment and self-renewal of SSCs in developing BM in vivo occurs via specific, dynamic interactions with developing sinusoids. Non-differentiated SSCs residing on the sinusoidal wall, but not differentiated osteoblasts, express Angiopoietin-1 (a pivotal molecule of the HSC "niche" involved in vascular remodeling). Our data reveal the functional relationships between establishment of the HME in vivo, establishment of SSCs in BM sinusoids, and angiogenesis. Keywords: comparative genomics, genetic modification

2007-12-06 | GSE6460 | GEO

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