Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Post-resolution macrophage-derived lipids shapes long-term tissue immunity and integrity

ABSTRACT: Resolving inflammation is thought to return the affected tissue back to homeostasis. However, we show that within days following resolution of Streptococcus pneumonia-triggered lung inflammation there is an influx of antigen specific lymphocytes with a memory and tissue-resident phenotype as well as macrophages bearing an alveolar or interstitial phenotype. Transcriptomic analysis revealed that macrophages are enriched with genes that drive T cell chemotaxis and differentiation as well as prostaglandin biosynthesis. Therapeutic depletion of post-resolution macrophages, inhibition of PGE2 synthesis or antagonism of EP4 reduced numbers of lung CD4+/CD44+/CD62L+ and CD4+/CD44+/CD62L-/CD27+ T cells as well as their expression of the a-integrin, CD103. This intervention resulted in a failure of these cells to reappear and reactivate upon secondary challenge up to six weeks following primary infection. Concomitantly, EP4 antagonism caused accumulation of lung macrophages and marked tissue fibrosis. Hence, resolving inflammation triggers a second wave of immune activity controlled, in part, by PGE2, which through EP4, drives local tissue-resident T cell development on the one hand, whilst limiting tissue injury on the other

ORGANISM(S): Mus musculus

PROVIDER: GSE264058 | GEO | 2024/04/17

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Effect of PGE2 pathway antagonists on APCmin/+ small intestine polyps

Project description:While the role of prostaglandin E2 (PGE2) in promoting malignant progression is well-established, how to optimally block the activity of PGE2 signaling remains to be demonstrated. Clinical trials with prostaglandin pathway targeted agents have shown activity but without sufficient significance or dose-limiting toxicities that have prevented approval. PGE2 signals through four receptors (EP1-4) to modulate tumor progression. EP2 and EP4 signaling exacerbates tumor pathology and is immunosuppressive through potentiating cAMP production. EP1 and EP3 signaling has the opposite effect through increasing IP3 and decreasing cAMP. Using available small molecule antagonists of single EP receptors, the COX-2 inhibitor celecoxib, or a novel dual EP2/EP4 antagonist generated in this investigation, we tested which approach to block PGE2 signaling optimally restored immunologic activity in mouse and human immune cells and antitumor activity in syngeneic, spontaneous and xenograft tumor models. We found that dual antagonism of EP2 and EP4 together significantly enhanced the activation of PGE2-suppressed mouse and human monocytes and CD8+ T cells in vitro as compared to single EP antagonists. CD8+ T cell activation was dampened by single EP1 and EP3 antagonists. Dual EP2/EP4 PGE2 receptor antagonists increased TME lymphocyte infiltration and significantly reduced disease burden in multiple tumor models, including in the adenomatous polyposis coli (APC)min+/- spontaneous colorectal tumor model, compared to celecoxib. These results support a hypothesis that redundancy of EP2 and EP4 receptor signaling necessitates a therapeutic strategy of dual blockade of EP2 and EP4. Here we describe TPST-1495, a first-in-class orally available small molecule dual EP2/EP4 antagonist.

2023-08-21 | GSE229806 | GEO

Microglial response to A? and prostaglandin-E2 EP4 receptor activation

Project description:A persistent and non-resolving inflammatory response to accumulating A? peptide species is a cardinal feature in the development of Alzheimer's disease (AD). In response to accumulating A? peptide species, microglia, the innate immune cells of the brain, generate a toxic inflammatory response that accelerates synaptic and neuronal injury. Many pro-inflammatory signaling pathways are linked to progression of neurodegeneration. However, endogenous anti-inflammatory pathways capable of suppressing A?-induced inflammation represent a relatively unexplored area. Here we hypothesized that signaling through the prostaglandin-E2 (PGE2) EP4 receptor potently suppresses microglial inflammatory responses to A?42 peptides. In cultured microglial cells, EP4 stimulation attenuated levels of A?42-induced inflammatory factors and potentiated phagocytosis of A?42. Microarray analysis was performed and demonstrated that EP4 stimulation broadly opposed A?42-driven gene expression changes in microglia, with enrichment for targets of IRF1, IRF7, and NF-?B transcription factors. Primary microglia were isolated from the brains of postnatal day 7 C57BL/6J mouse pups using the Neural Tissue Dissociation Kit (P), MACS Separation Columns (LS), and magnetic CD11b Microbeads from Miltenyi Biotec (Auburn, CA). Microglia from three separate litters of pups were maintained as three independent biological replicates for each treatment. After being cultured for three days, microglia were treated with oligomeric A?42 (10uM) and/or the specific EP4 agonist AE1-329 (100nM) for 6 hours. These 4 treatment conditions (A? + AE1, A? alone, AE1 alone, and vehicle alone) and 3 independent biological replicates per treatment gave us 12 total samples. After 6 hours of treatment, RNA was isolated from the microglia for microarray analysis.

2014-04-25 | E-GEOD-55627 | biostudies-arrayexpress

T cell-intrinsic prostaglandin E2-EP2/EP4 signaling is critical in pathogenic Th17 cell-driven inflammation

Project description:IL-23 induces ptgs2 encoding cyclooxygenase 2 in Th17 cells and produces PGE2, which acts back on PGE2 receptors EP2 and EP4 in these cells and enhances IL-23-induced expression of an IL-23 receptor subunit gene, Il23r, by activating STAT3, CREB1 and NF-κB through cAMP-protein kinase A signaling. This PGE2 signaling also induces expression of various inflammation-related genes, which possibly function in Th17 cell-mediated pathology. Combined deletion of EP2 and EP4 selectively in T cells suppressed accumulation of IL-17A+ and IL-17A+IFN-γ+ pathogenic Th17 cells and abolished skin inflammation in IL-23-induced psoriasis mouse model. Analysis of human psoriatic skin biopsies shows positive correlation between PGE2 signaling and the IL-23/Th17 pathway.

2021-02-23 | GSE167248 | GEO

Mutual Antagonistic Relationship Between Prostaglandin E2 and Interferon-(gamma): Implications for Rheumatoid Arthritis

Project description:PGE2 is a major mediator of inflammation and is present at high concentrations in the synovial fluid of rheumatoid arthritis (RA) patients. PGE2, acting through the EP4 receptor, has both pro- and anti-inflammatory roles in vivo. To shed light on this dual role of PGE2, we investigated its effects in whole blood and in primary human fibroblast-like synoviocytes. Gene expression analysis in human leukocytes, confirmed at the protein level, revealed an EP4-dependent inhibition of the expression of genes involved in the IFN-gamma activation pathway, including IFN-gamma itself. This effect of the PGE2/EP4 axis on IFN-gamma is a reciprocal phenomenon since IFN-gamma blocks PGE2 release and blocks EP receptor expression. The mutually antagonistic relationship between IFN-gamma and PGE2 extends to downstream cytokine- and chemokine-release; PGE2 counters the effects of IFN-gamma, on the release of IP-10, IL-8, TNFalpha and IL-1beta. To gain further insight into IFN-gamma-mediated cellular events in rheumatoid arthritis, we assessed the effects of IFN-gamma on gene expression in fibroblast-like synoviocytes. We observed an IFN-gamma-dependent up-regulation of macrophage-attracting chemokines, and down-regulation of metalloprotease expression. These results suggest the existence of a mutually antagonistic relationship between PGE2 and IFN-gamma which may represent a fundamental mechanism of immune control in diseases such as RA. For details, see Mathieu MC et al, EJI, issue 7, 2008

2008-05-29 | E-GEOD-11575 | biostudies-arrayexpress

Microglial response to Aβ and prostaglandin-E2 EP4 receptor activation

Project description:A persistent and non-resolving inflammatory response to accumulating Aβ peptide species is a cardinal feature in the development of Alzheimer's disease (AD). In response to accumulating Aβ peptide species, microglia, the innate immune cells of the brain, generate a toxic inflammatory response that accelerates synaptic and neuronal injury. Many pro-inflammatory signaling pathways are linked to progression of neurodegeneration. However, endogenous anti-inflammatory pathways capable of suppressing Aβ-induced inflammation represent a relatively unexplored area. Here we hypothesized that signaling through the prostaglandin-E2 (PGE2) EP4 receptor potently suppresses microglial inflammatory responses to Aβ42 peptides. In cultured microglial cells, EP4 stimulation attenuated levels of Aβ42-induced inflammatory factors and potentiated phagocytosis of Aβ42. Microarray analysis was performed and demonstrated that EP4 stimulation broadly opposed Aβ42-driven gene expression changes in microglia, with enrichment for targets of IRF1, IRF7, and NF-κB transcription factors.

2014-04-25 | GSE55627 | GEO

Transcriptome profiles of pancreatic macrophage following AP injury

Project description:Upon injury, immune cells undergo dynamic changes in population size, differentiation state and function in response to maintain organismal integrity. Myeloid cells, mostly macrophages have been shown to act as positive regulators of development, tissue homoeostasis, inflammation，especially in inducing resolution after inflammation, remodeling and repair. Here we report what specific role macrophages play in every precisely dynamical period after injury in vivo. We first confirmed that M2-like macrophages from recruited monocytes accumulate during AP recovery(RAP). By macrophage depletion in different time points, before or after ADM phase, we elucidate distinct roles of macrophage in different stages of AP recovery. To further understanding the phenotype and function of macrophage during AP recovery, pancreatic macrophages were isolated in all precisely indicated time points for RNA-seq analysis. By analyzing RNA-seq result, we verify PI3K-AKT activation in macrophage aids in resolving inflammation in ADM phase and IL4RA deficiency impairs M2-like macrophages and AP recovery. Finally, we further investigated PGE2’s role in regulating M2 macrophage polarization and we found PGE2 augments IL4Ra signaling to enhance M2 activation of macrophage.

2020-08-10 | GSE138134 | GEO

Expression profiles of primary bone marrow derived mouse macrophages M-bM-^@M-^S untreated and treated with LPS or LPS+PGE

Project description:The polarization of macrophages into an anti-inflammatory or regulatory phenotype plays an important role in resolving inflammation. PGE2 regulates macrophage polarization via a PKA dependent pathway. PKA phosphorylates SIKs, inhibiting their ability to phosphorylate CRTC3 in cells. This in turn allows CRTC3 to translocate to the nucleus where it acts as a co-activator with the transcription factor CREB to induce IL-10 transcription. In line with this we find that either genetic or pharmacological inhibition of SIKs mimics the effect of PGE2 on IL-10 production. We show here that PGE2, in combination with LPS, is able to promote a regulatory like phenotype in macrophages characterized by high expression of IL-10 as well as the regulatory markers SPHK1 and LIGHT. Gene expression profiles of primary bone marrow derived mouse macrophages treated with LPS or LPS+PGE and untreated controls were generated using Affymetrix mouse gene 1.1 ST arrays. In total, 12 arrays were generated from the three groups (LPS, LPS+PGE and control) with 4-replicates in each group. One sample from LPS group was removed due to QC issues and the remaining 11 that were used in our analyses are submitted here.

2013-02-06 | E-GEOD-41833 | biostudies-arrayexpress

Mutual Antagonistic Relationship Between Prostaglandin E2 and Interferon-(gamma): Implications for Rheumatoid Arthritis

2008-05-29 | GSE11575 | GEO

Expression profiles of primary bone marrow derived mouse macrophages – untreated and treated with LPS or LPS+PGE

2013-02-06 | GSE41833 | GEO

Thrombocytes-derived Dickkopf1 promotes wound-healing macrophage polarization

Project description:Immune responses are crucial to maintaining tissue homeostasis upon tissue injury. Upon various types of challenges, macrophages play a central role in regulating inflammation and tissue repair processes. While an immunomodulatory role of Wnt antagonist Dickkopf1 (DKK1) has been implicated, the role of Wnt antagonist DKK1 in regulating macrophage polarization in inflammation and the tissue repair process remains elusive. Here we found that DKK1 induces differential gene expression profiles from type 2-cytokine-activated macrophages to promote inflammation and tissue repair. Importantly, DKK1 induced pro-inflammatory and pro-resolving gene expressions via JNK (c-jun N-terminal kinase) in macrophages. Furthermore, DKK1 potentiated IL-13-mediated macrophage polarization and activation. Co-inhibition of JNK and STAT6 markedly decreased pro-inflammatory and pro-resolving gene expressions by DKK1 and IL-13. Interestingly, thrombocyte-specific deletion of DKK1 in mice reduced monocyte-derived macrophages in the acute sterile bleomycin (BLM)-induced lung injury model, suggesting that thrombocytes communicate with macrophages via DKK1 to orchestrate inflammation-induced injury repair process. Taken together, our study demonstrates DKK1’s role as a key regulatory role in macrophage polarization in the injury-induced inflammation and repair process.

2023-12-06 | GSE247398 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data