Mus musculus
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ABSTRACT:
PROVIDER: PRJNA102401 | ENA |
REPOSITORIES: ENA
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Project description:Recognition and response to gram-positive bacteria by macrophages and dendritic cells is mediated in part through TLR2. We found that that Streptococcus pneumoniae cell wall fragments, containing primarily peptidoglycan and teichoic acids, induced prodigious secretion of IL-10 from macrophages and dendritic cells and was dependent on TLR2 and NOD2, a cytoplasmic CARD-NACHT-LRR protein encoded by Card15. IL-10 secretion in response to cell walls was also dependent on RICK/RIP2, a kinase associated with NOD2, and MYD88 but independent of the ERK/p38 pathway. The reduction of IL-10 secretion by cell wall-activated NOD2-deficient myeloid–derived cells translated into downstream effects on IL-10 target gene expression and elevations in subsets of pro-inflammatory cytokine expression normally restrained by autocrine/paracrine effects of IL-10. Since NOD2 is linked to aberrant immune responses in Crohn’s Disease patients bearing mutations in CARD15, the temporal and quantitative effects of the TLR2/NOD/RICK pathway on IL-10 secretion may affect homeostatic control of immune responses to gram-positive bacteria. Keywords: immune response simulated pathogen response
2008-09-01 | GSE8960 | GEO
Project description:Recognition and response to gram-positive bacteria by macrophages and dendritic cells is mediated in part through TLR2. We found that that Streptococcus pneumoniae cell wall fragments, containing primarily peptidoglycan and teichoic acids, induced prodigious secretion of IL-10 from macrophages and dendritic cells and was dependent on TLR2 and NOD2, a cytoplasmic CARD-NACHT-LRR protein encoded by Card15. IL-10 secretion in response to cell walls was also dependent on RICK/RIP2, a kinase associated with NOD2, and MYD88 but independent of the ERK/p38 pathway. The reduction of IL-10 secretion by cell wall-activated NOD2-deficient myeloidâderived cells translated into downstream effects on IL-10 target gene expression and elevations in subsets of pro-inflammatory cytokine expression normally restrained by autocrine/paracrine effects of IL-10. Since NOD2 is linked to aberrant immune responses in Crohnâs Disease patients bearing mutations in CARD15, the temporal and quantitative effects of the TLR2/NOD/RICK pathway on IL-10 secretion may affect homeostatic control of immune responses to gram-positive bacteria. Experiment Overall Design: KO mice were treated with a cel wall extract and evaluated for immune response 1 hr and 4 hrs after treatment
2008-10-25 | E-GEOD-8960 | biostudies-arrayexpress
Project description:Microglia are the resident mononuclear phagocytes of the CNS parenchyma and represent an initial line of defense against invading microorganisms. Microglia utilize Toll-like receptors (TLRs) for pathogen recognition and TLR2 specifically senses conserved motifs of gram-positive bacteria including lipoproteins, lipoteichoic acids, and peptidoglycan (PGN) leading to cytokine/chemokine production. Interestingly, primary microglia derived from TLR2 knockout (KO) mice over-expressed numerous IL-12 family members, including IL-12p40, IL-12p70, and IL-27 in response to intact S. aureus, but not the less structurally complex TLR2 ligands Pam3CSK4 or PGN. The ability of intact bacteria to augment IL-12 family member expression was specific for gram-positive organisms, since numerous gram-negative strains were unable to elicit exaggerated responses in TLR2 KO microglia. Inhibition of SYK or IRAK4 signaling did not impact heightened IL-12 family member production in S. aureus-treated TLR2 KO microglia, whereas PI3K, MAPK, and JNK inhibitors were all capable of restoring exaggerated cytokine expression to wild type levels. Additionally, elevated IL-12 production in TLR2 KO microglia was ablated by a TLR9 antagonist, suggesting that TLR9 drives IL-12 family member production following exposure to intact bacteria that remains unchecked in the absence of TLR2 signaling. Collectively, these findings indicate crosstalk between TLR2 and TLR9 pathways to regulate IL-12 family member production by microglia. The summation of TLR signals must be tightly controlled to ensure the timely cessation and/or fine tuning of cytokine signaling to avoid nonspecific bystander damage due to sustained IL-12 release.
2014-12-22 | GSE24935 | GEO
Project description:Microglia are the resident mononuclear phagocytes of the CNS parenchyma and represent an initial line of defense against invading microorganisms. Microglia utilize Toll-like receptors (TLRs) for pathogen recognition and TLR2 specifically senses conserved motifs of gram-positive bacteria including lipoproteins, lipoteichoic acids, and peptidoglycan (PGN) leading to cytokine/chemokine production. Interestingly, primary microglia derived from TLR2 knockout (KO) mice over-expressed numerous IL-12 family members, including IL-12p40, IL-12p70, and IL-27 in response to intact S. aureus, but not the less structurally complex TLR2 ligands Pam3CSK4 or PGN. The ability of intact bacteria to augment IL-12 family member expression was specific for gram-positive organisms, since numerous gram-negative strains were unable to elicit exaggerated responses in TLR2 KO microglia. Inhibition of SYK or IRAK4 signaling did not impact heightened IL-12 family member production in S. aureus-treated TLR2 KO microglia, whereas PI3K, MAPK, and JNK inhibitors were all capable of restoring exaggerated cytokine expression to wild type levels. Additionally, elevated IL-12 production in TLR2 KO microglia was ablated by a TLR9 antagonist, suggesting that TLR9 drives IL-12 family member production following exposure to intact bacteria that remains unchecked in the absence of TLR2 signaling. Collectively, these findings indicate crosstalk between TLR2 and TLR9 pathways to regulate IL-12 family member production by microglia. The summation of TLR signals must be tightly controlled to ensure the timely cessation and/or fine tuning of cytokine signaling to avoid nonspecific bystander damage due to sustained IL-12 release. TLR2 KO mice were backcrossed with C57BL/6 animals for a minimum of eight generations prior to use in these studies. Age- and sex-matched C57BL/6 mice were used as wild type (WT) controls. Primary mixed glial cultures were prepared from the cerebral corticies of neonatal mice (2-4 days of age) and microglia were harvested using a differential shaking technique with a purity of >98%. A USA300 community-acquired methicillin-resistant S. aureus (CA-MRSA) clinical isolate recovered from a patient with a fatal brain abscess was used to stimulate the microglia isolates. Bacterial strains were heat-inactivated and used to stimulate microglia at 107 colony forming units (cfu)/well for 6 and 12 hours time points. Three replicates of each mouse type (WT, TLR2 KO) at both time points 6 and 12 hours were used for the microarray experiments. Data was only usable for 2 replicates of the KO-12 hr group.
2014-12-22 | E-GEOD-24935 | biostudies-arrayexpress
Project description:Neutrophil abscess formation is critical in innate immunity against many pathogens. Here, the mechanism of neutrophil abscess formation was investigated using a mouse model of Staphylococcus aureus cutaneous infection. Gene expression analysis of S. aureus-infected skin revealed that induction of neutrophil recruitment genes was largely dependent upon IL-1beta/IL-1R activation. Unexpectedly, using IL 1beta reporter mice, neutrophils were identified as the primary source of IL-1beta at the site of infection. Furthermore, IL-1beta-producing neutrophils were necessary and sufficient for abscess formation and bacterial clearance. S. aureus-induced IL 1beta production by neutrophils required TLR2, NOD2, FPRs and the ASC/NLRP3 inflammasome. Taken together, IL-1beta and neutrophil abscess formation during an infection are functionally, spatially and temporally linked as a consequence of direct IL-1beta production by neutrophils. Lesional skin biopsies obtained from C57BL/6J WT mice or IL-1R-deficient mice at 4 hours post-infection with Staphylococcus aureus. Uninfected skin biopsies were also collected from WT and IL-1R-deficient mice.
2012-12-05 | E-GEOD-36826 | biostudies-arrayexpress
Project description:Neutrophil abscess formation is critical in innate immunity against many pathogens. Here, the mechanism of neutrophil abscess formation was investigated using a mouse model of Staphylococcus aureus cutaneous infection. Gene expression analysis of S. aureus-infected skin revealed that induction of neutrophil recruitment genes was largely dependent upon IL-1beta/IL-1R activation. Unexpectedly, using IL 1beta reporter mice, neutrophils were identified as the primary source of IL-1beta at the site of infection. Furthermore, IL-1beta-producing neutrophils were necessary and sufficient for abscess formation and bacterial clearance. S. aureus-induced IL 1beta production by neutrophils required TLR2, NOD2, FPRs and the ASC/NLRP3 inflammasome. Taken together, IL-1beta and neutrophil abscess formation during an infection are functionally, spatially and temporally linked as a consequence of direct IL-1beta production by neutrophils.
2012-12-05 | GSE36826 | GEO
Project description:IL-10 is produced by macrophages in diverse immune settings and is critical in limiting immune-mediated pathology. In helminth infections macrophages are an important source of IL-10, however the molecular mechanism underpinning production of IL-10 by these cells is poorly characterized. Here, bone marrow derived macrophages exposed to Excretory/Secretory (E/S) products released by Schistosoma mansoni cercariae rapidly produce IL-10 as a result of MyD88-mediated activation of MEK/ERK/RSK and p38. The phosphorylation of these kinases was triggered by TLR2 and TLR4 and converged on activation of the transcription factor CREB. Uptake of cercarial E/S products by phagocytosis was critical for the production of IL-10 and the activation of MAPKs and CREB, which indicates that interactions between E/S products with TLR2 and TLR4, may be occurring in endosomes. Following phosphorylation, CREB is recruited to a novel regulatory element in the Il10 promoter and is also responsible for regulating a network of genes involved in metabolic processes, such as glycolysis, the tricarboxylic acid cycle and oxidative phosphorylation. Moreover, skin resident tissue macrophages, which encounter S. mansoni E/S products during infection, are the first monocytes to produce IL-10 in vivo early after infection with S. mansoni cercariae. The early and rapid release of IL-10 by these cells has the potential to condition the dermal microenvironment encountered by immune cells recruited to this infection site. To conclude, we propose a mechanism by which CREB regulates the production of IL-10 by macrophages in the skin, but also has a major effect on their metabolic state. CREB binding sites 3 pooled samples of stimulated bone marrow macrophages
2015-07-08 | E-GEOD-64844 | biostudies-arrayexpress
Project description:IL-10 regulates anti-inflammatory signaling via the activation of STAT3, which in turn controls the induction of a gene expression program whose products execute inhibitory effects on pro-inflammatory mediator production. Here we show that IL-10 induces the expression of an ETS family transcriptional repressor, ETV3 and a helicase family co-repressor, SBNO2 (Strawberry notch homolog 2) in mouse and human macrophages. IL-10-mediated induction of ETV3 and SBNO2 expression was dependent upon both STAT3, and co-stimulus through the TLR pathway. We also observed that ETV3 expression was strongly induced by the STAT3 pathway induced by IL-10 but not STAT3 signaling activated by IL-6, which cannot activate the anti-inflammatory signaling pathway. ETV3 and SBNO2 specifically repressed NF-kB-mediated transcription and can physically interact. Collectively our data suggest that ETV3 and SBNO2 are components of the pathways that contribute to the downstream anti-inflammatory effects of IL-10. We compared expression profiles of macrophages isolated from IL-10 -/- mice. Macrophages were treated with either LPS or LPS plus IL-10. Treatment times were 10, 20 and 30 minutes. Keywords: time-course, treatment response, gene expression analysis
2007-12-01 | GSE9509 | GEO
Project description:IL-10 regulates anti-inflammatory signaling via the activation of STAT3, which in turn controls the induction of a gene expression program whose products execute inhibitory effects on pro-inflammatory mediator production. Here we show that IL-10 induces the expression of an ETS family transcriptional repressor, ETV3 and a helicase family co-repressor, SBNO2 (Strawberry notch homolog 2) in mouse and human macrophages. IL-10-mediated induction of ETV3 and SBNO2 expression was dependent upon both STAT3, and co-stimulus through the TLR pathway. We also observed that ETV3 expression was strongly induced by the STAT3 pathway induced by IL-10 but not STAT3 signaling activated by IL-6, which cannot activate the anti-inflammatory signaling pathway. ETV3 and SBNO2 specifically repressed NF-kB-mediated transcription and can physically interact. Collectively our data suggest that ETV3 and SBNO2 are components of the pathways that contribute to the downstream anti-inflammatory effects of IL-10. We compared expression profiles of macrophages isolated from IL-10 -/- mice. Macrophages were treated with either LPS or LPS plus IL-10. Treatment times were 10, 20 and 30 minutes. Experiment Overall Design: Mouse IL-10 -/- macrophages were isolated and purified and set up in culture medium containing LPS or LPS plus IL-10. A total of 18 samples were analyzed. This set contains three replicates of each treatment condition where treatment (LPS versus LPS plus IL-10) and time (10min, 20min and 30min) were varied.
2008-06-16 | E-GEOD-9509 | biostudies-arrayexpress
Project description:Glycosylation-dependent modulation of the IL-2 signaling axis determines Th17 differentiation and IL-10 production
| PRJNA529801 | ENA