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IL-10 production and metabolic regulation in macrophages are linked by a TLR-driven CREB-mediated mechanism

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE64844 | GEO | 2015/07/08

SECONDARY ACCESSION(S): PRJNA272149

REPOSITORIES: GEO

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IL-10 production and metabolic regulation in macrophages are linked by a TLR-driven CREB-mediated mechanism

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

Alternatively activated mononuclear phagocytes from the skin site of infection and the impact of IL-4RÎ± signaling on CD4+T cell survival in draining lymph nodes after repeated exposure to Schistosoma mansoni cercariae

Project description:In areas endemic for schistosomiasis, repeated exposure to infective cercariae is a frequent occurrence, and repeated exposure of murine skin to Schistosoma mansoni resulted in CD4+ T cells becoming hypo-responsive. Here potential contributory mechanisms were investigated. In the skin infection site, three mononuclear phagocyte populations were identified (tissue macrophages, dendritic cells, and macrophages) which exhibited up-regulation of genes associated with alternative activation, in particular the gene encoding RELMÎ±. However, in repeatedly infected mice deficient in RELMÎ±, there was no change in the abundance of mononuclear phagocytes in the skin, and CD4+ cells in the skin draining lymph nodes remained hypo-responsive. In mice deficient for IL-4RÎ±, required for alternative activation, levels of dermal regulatory IL-10 were reduced and there was an increase in the abundance of antigen presenting MHC-IIhigh cells, which was accompanied by increased numbers of CD4+ T cells. Although the absence of IL-4RÎ± did not translate into increased CD4+ cell responsiveness, they exhibited lower expression of Fas/FasL, resulting in decreased apoptosis/cell death and increased cell viability. This study highlights a mechanism through which IL-4RÎ± may regulate the immune system through the induction of IL-10 and regulation of Fas/FasL mediated cell death. Mice were infected 1x or 4x with S. mansoni cercariae via the pinnae. Pinnae were harvested 4 days after the final infection and the DEC obtained after an overnight culture in vitro. Cells were then stained with F4/80 APC and MHC-II PE and four different populations sorted (using the MoFlo or the Astrios) based on their expression profiles. Several mice (12-18) from each group were pooled to generate each replicate.

2016-07-26 | E-GEOD-81938 | biostudies-arrayexpress

Differential production of Type I IFN determines the reciprocal levels of IL-10 and proinflammatory cytokines produced by C57BL/6 and BALB/c macrophages

Project description:Pattern recognition receptors (PRR) detect microbial products and induce cytokines which shape the immunological response. Interleukin-12 (IL-12), tumor necrosis factor alpha (TNF-Î±) and IL-1Î² are proinflammatory cytokines which can be essential for resistance against infection, but if produced at high levels, may contribute to immunopathology. In contrast, IL-10 is an immunosuppressive cytokine which dampens proinflammatory responses, but can also lead to defective pathogen clearance. The regulation of these cytokines is therefore central to the generation of an effective but balanced immune response. Here, we show that macrophages derived from C57BL/6 mice produce low levels of IL-12, TNF-Î± and IL-1Î², but high levels of IL-10 in response to TLR4 and TLR2 ligands LPS and PamCSK4, and Burkholderia pseudomallei a Gram-negative bacterium which activates TLR 2/4. In contrast, macrophages derived from BALB/c mice show a reciprocal pattern of cytokine production. Differential production of IL-10 in B. pseudomallei and LPS stimulated C57BL/6 and BALB/c macrophages was due to a type I IFN dependent, but IL-27 independent mechanism. Further, type I IFN contributed to differential IL-1Î² and IL-12 production in B. pseudomallei and LPS stimulated C57BL/6 and BALB/c macrophages, via both IL-10-dependent and independent mechanisms. These findings highlight key pathways responsible for the regulation of pro- and anti-inflammatory cytokines in macrophages and reveal how they may differ according to the genetic background of the host. Total RNA obtained from bone-marrow derived macrophages of C57BL/6 WT, C57BL/6 Ifnar1-/- and BALB/c mice stimulated with heat-killed Burkholderia pseudomallei or media as controls.

2016-09-07 | E-GEOD-79809 | biostudies-arrayexpress

Differential production of Type I IFN determines the reciprocal levels of IL-10 and proinflammatory cytokines produced by C57BL/6 and BALB/c macrophages

Project description:Pattern recognition receptors (PRR) detect microbial products and induce cytokines which shape the immunological response. Interleukin-12 (IL-12), tumor necrosis factor alpha (TNF-α) and IL-1β are proinflammatory cytokines which can be essential for resistance against infection, but if produced at high levels, may contribute to immunopathology. In contrast, IL-10 is an immunosuppressive cytokine which dampens proinflammatory responses, but can also lead to defective pathogen clearance. The regulation of these cytokines is therefore central to the generation of an effective but balanced immune response. Here, we show that macrophages derived from C57BL/6 mice produce low levels of IL-12, TNF-α and IL-1β, but high levels of IL-10 in response to TLR4 and TLR2 ligands LPS and PamCSK4, and Burkholderia pseudomallei a Gram-negative bacterium which activates TLR 2/4. In contrast, macrophages derived from BALB/c mice show a reciprocal pattern of cytokine production. Differential production of IL-10 in B. pseudomallei and LPS stimulated C57BL/6 and BALB/c macrophages was due to a type I IFN dependent, but IL-27 independent mechanism. Further, type I IFN contributed to differential IL-1β and IL-12 production in B. pseudomallei and LPS stimulated C57BL/6 and BALB/c macrophages, via both IL-10-dependent and independent mechanisms. These findings highlight key pathways responsible for the regulation of pro- and anti-inflammatory cytokines in macrophages and reveal how they may differ according to the genetic background of the host.

2016-09-07 | GSE79809 | GEO

RNA-seq analysis of IL-10 treatment of wildtype and Ptpn1-/- knockout peritoneal macrophages

Project description:We report here the deep sequencing of the mRNA from peritoneal exudate cells (macrophages) purified from wildtype or Ptpn1 (PTP1B) knockout mice, either treated or untreated with IL-10. In periotenal macrophages IL-10 activates the transcription factor STAT3 to execute and anti-inflammatory gene expression programme. The tyrosine phosphatase PTPN1 targets STAT3 for dephosphorylation and leads to the deactivation of STAT3. In this study we examined the role of PTP1B in controlling the normal homeostatic level phosphorylation of STAT3 by comparing the IL-10/STAT3-mediated anti-inflammatory gene expression programme. We find that loss of PTP1B leads to an up-regulation of the activity of STAT3, both at the level of phosphorylation and also in enhanced expression of anti-inflammatory gene products. RNA-seq of wildtype and Ptpn1 (PTP1B) knockout mouse peritoneal macrophages, treated or untreated with IL-10

2014-05-12 | E-GEOD-49449 | biostudies-arrayexpress

Alternatively activated mononuclear phagocytes from the skin site of infection and the impact of IL-4Rα signaling on CD4+T cell survival in draining lymph nodes after repeated exposure to Schistosoma mansoni cercariae

Project description:In areas endemic for schistosomiasis, repeated exposure to infective cercariae is a frequent occurrence, and repeated exposure of murine skin to Schistosoma mansoni resulted in CD4+ T cells becoming hypo-responsive. Here potential contributory mechanisms were investigated. In the skin infection site, three mononuclear phagocyte populations were identified (tissue macrophages, dendritic cells, and macrophages) which exhibited up-regulation of genes associated with alternative activation, in particular the gene encoding RELMα. However, in repeatedly infected mice deficient in RELMα, there was no change in the abundance of mononuclear phagocytes in the skin, and CD4+ cells in the skin draining lymph nodes remained hypo-responsive. In mice deficient for IL-4Rα, required for alternative activation, levels of dermal regulatory IL-10 were reduced and there was an increase in the abundance of antigen presenting MHC-IIhigh cells, which was accompanied by increased numbers of CD4+ T cells. Although the absence of IL-4Rα did not translate into increased CD4+ cell responsiveness, they exhibited lower expression of Fas/FasL, resulting in decreased apoptosis/cell death and increased cell viability. This study highlights a mechanism through which IL-4Rα may regulate the immune system through the induction of IL-10 and regulation of Fas/FasL mediated cell death.

2016-07-26 | GSE81938 | GEO

The TLR2/NOD2/RICK signaling axis regulates stimulus-specific IL-10 production

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

Biomphalaria glabrata haemocytes vs ESPs

Project description:During its life cycle, the helminth parasite Schistosoma mansoni uses the freshwater snail Biomphalaria glabrata as an intermediate host to reproduce asexually generating cercariae for infection of the human definitive host. Following invasion of the snail, the parasite develops from a miracidium to a mother sporocyst and releases excretory secretory products (ESPs) that likely influence the outcome of host infection. To better understand molecular interactions between these ESPs and the host snail defence system, we determined gene expression profiles of haemocytes from S. mansoni resistant or -susceptible strains of B. glabrata exposed in vitro to S. mansoni ESPs (20ug/ml) for 1 h, using a 5K B. glabrata cDNA microarray.

2014-12-31 | E-MTAB-2135 | biostudies-arrayexpress

RNA-seq analysis of IL-10 treatment of wildtype and Ptpn1-/- knockout peritoneal macrophages

2014-05-12 | GSE49449 | GEO

Transcription profiling of mouse knockouts reveals the TLR2/NOD2/RICK signaling axis regulates stimulus-specific IL-10 production

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

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