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Gene expression analysis of PBMC's from IBD subjects stimulated by combinations of LPS, MDP, anti-CD3/anti-CD28 antibodies, and anti-IL10R antibodies.

ABSTRACT: We systematically investigated the transcriptomic response pattern of PBMC from 41 patients with IBD to characterize relevant stimuli that target different aspects of innate and adaptive immune cell responses. Lipopolysaccharide(LPS), muramyl-dipeptide (L18MDP), T cell receptor and co-stimulation (αCD3/αCD28 coated beads), and IL-10 signalling blockade were used to sitmulate subject PBMC's alone or in combination based on the concept that innate pathogen recognition receptor responses (in particular NOD2 and TLR4), T cell responses, and IL-10 signalling defects are implicated by multiple genetic IBD susceptibility loci and Mendelian forms of IBD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE137680 | GEO | 2020/08/01

REPOSITORIES: GEO

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Gene expression analysis of PBMC's from IBD subjects stimulated by combinations of LPS, MDP, anti-CD3/anti-CD28 antibodies, and anti-IL10R antibodies.

Project description:Gene expression analysis of PBMC's from IBD subjects stimulated by combinations of LPS, MDP, anti-CD3/anti-CD28 antibodies, and anti-IL10R antibodies.

| PRJNA574128 | ENA

Expression analysis of human PBMCs stimulated with Borrelia, MDP or Pam3cys.

Project description:Analysis examining the effect of the Crohn's disease-associated ATG16L1 polymorphism on the responses to stimulation components derived from various bacteria classes. Expression analysis was performed on RNA extracted from peripheral blood mononuclear cells (PBMCs) from healthy genotyped volunteers were stimulated for 24h with RPMI alone, or RPMI containing heat-killed Borrelia burgdorferi , muramyl dipeptide (MDP) or Pam3Cys.

2015-06-30 | E-GEOD-68765 | biostudies-arrayexpress

MDP phosphorylation by NAGK is essential for NOD2 activation

Project description:Bacterial cell wall components provide various unique molecular structures that are detected by pattern recognition receptors (PRRs) of the innate immune system as non-self. Most bacterial species form a cell wall that consists of peptidoglycan, a polymeric structure comprising of alternating amino sugars. Muramyl dipeptide (MDP) is the minimal, biologically active molecular structure derived from peptidoglycan, and its immunogenicity is well documented in numerous studies. MDP is sensed by the cytosolic nucleotide-binding and nucleotide oligomerization domain-like receptor 2 (NOD2), which triggers a pro-inflammatory response upon engagement 1,2. Conducting a forward genetic screen to identify factors required for MDP detection, we discovered that N-acetylglucosamine kinase (NAGK) is essential for the immunostimulatory activity of MDP. NAGK, which has previously been identified to contribute to the hexosamine salvage pathway in humans, is broadly expressed and inducible in innate immune cells. Mechanistically, NAGK functions upstream of NOD2 in that it directly phosphorylates the N-acetylmuramic moiety of MDP at the hydroxyl group of its C6 position, yielding 6-O-phospho-MDP. NAGK-phosphorylated MDP constitutes an essential component of NOD2 dependent signal transduction. Altogether, these results unveil a previously unknown interconnection of amino sugar metabolism and innate immunity to bacterial cell walls.

2022-06-13 | PXD022384 | Pride

Bone marrow derived dendritic cells (BMDC) and MDP and MSU

Project description:Muramyl dipeptide (MDP) and Monosodium urate crystals (MSU) promote a synergistic effect on NOD2 and NLRP3 with a unique transcriptional profile in murine dendritic cells

2010-12-01 | E-MEXP-2905 | biostudies-arrayexpress

Transcription profiling of humuan peripheral blood mononuclear cells stimulated with interleukin-12 and unstimulated controls

Project description:The cytokine interleukin-12 (IL-12) is known to play a central role in adaptive and innate immunity. We employed microarray analysis of IL-12 induced gene expression to provide further insights into its effects on immune response. Experiment Overall Design: PBMC's were isolated from 7 healthy NIH blood bank donors. For each donor, expression levels were measured for PBMCs stimulated with IL-12 and for unstimulated controls, using the Affymetrix Human Genome HG-U133A and HG-U133B GeneChips.

2008-11-21 | E-GEOD-12839 | biostudies-arrayexpress

Therapeutic IL-6 trans-signalling inhibition by olamkicept (sgp130Fc) in patients with active inflammatory bowel disease

Project description:Background A large unmet therapeutic need exists in inflammatory bowel diseases (IBD). Inhibition of interleukin (IL)-6 appears to be effective, but the therapeutic benefit of a complete IL-6/IL-6R blockade is limited by profound immunosuppression. Evidence has emerged, that chronic pro-inflammatory activity of IL-6 is mainly mediated by trans-signalling via a complex of IL-6 bound to soluble IL-6R engaging the gp130 receptor without the need of membrane bound IL6R. We have developed a decoy protein, sgp130Fc, which exclusively blocks IL-6 pro-inflammatory trans-signalling and has shown efficacy in preclinical models of IBD, without signs of immunosuppression. Methods We present a 12-week, open label, prospective phase IIa trial (FUTURE) in 16 patients with active IBD treated with the trans-signalling inhibitor olamkicept (sgp130Fc) to assess molecular mechanisms, safety and effectiveness of IL-6 trans-signalling blockade in vivo. We performed in-depth molecular profiling at various time points before and after therapy induction to identify the mechanism of action of olamkicept. Results Olamkicept was well tolerated and induced clinical response in 44% and clinical remission in 19% of patients. Clinical effectiveness coincided with target inhibition (reduction of phosphorylated STAT3) and marked transcriptional changes in the inflamed mucosa. An olamkicept-specific transcriptional signature, distinguishable from remission signatures of anti-TNF (infliximab) or anti-integrin (vedolizumab) therapies was identified. Conclusion Our data suggest that blockade of IL-6 trans-signaling holds large promise for the therapy of IBD and should undergo full clinical development as a new immunoregulatory therapy of IBD.

2021-04-10 | GSE171770 | GEO

Docosahexaenoyl Serotonin, an endogenously formed n-3 fatty acid-serotonin conjugate, has anti-inflammatory properties by attenuating IL23–IL17 signalling in macrophages.

Project description:Conjugates of fatty acids and amines, including endocannabinoids, are known to play important roles as endogenous signalling molecules. Among these, the ethanolamine conjugate of the n-3 poly unsaturated long chain fatty acid (PUFA) docosahexaenoic acid (22:6n-3) (DHA) was shown to possess strong anti-inflammatory properties. Previously, we identified the serotonin conjugate of DHA, docosahexaenoyl serotonin (DHA-5-HT), in intestinal tissues and showed that its levels are markedly influenced by intake of n-3 PUFAs. However, its biological roles remain to be elucidated. Here, we show that DHA-5-HT possesses potent anti-inflammatory properties by attenuating the IL-23-IL-17 signalling cascade in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Transcriptome analysis revealed that DHA-5-HT down-regulates LPS-induced genes, particularly those involved in generating a CD4 + Th17 response. Hence, levels of PGE2, IL-6, IL-1β, and IL-23, all pivotal macrophage-produced mediators driving the activation of pathogenic Th17 cells in a concerted way, were found to be significantly suppressed by concentrations as low as 100–500 nM DHA-5-HT. Furthermore, DHA-5-HT inhibited the ability of RAW264.7 cells to migrate and downregulated chemokines like MCP-1, CCL-20, and gene-expression of CCL-22 and of several metalloproteinases. Gene set enrichment analysis (GSEA) suggested negative overlap with gene sets linked to inflammatory bowel disease (IBD) and positive overlap with gene sets related to the Nrf2 pathway. The specific formation of DHA-5-HT in the gut, combined with increasing data underlining the importance of the IL-23-IL-17 signalling pathway in the aetiology of many chronic inflammatory diseases merits further investigation into its potential as therapeutic compound in e.g. IBD or intestinal tumorigenesis.

2016-09-27 | GSE87369 | GEO

Complementary Phosphoproteomic Approaches Link IL-23R Downstream Signaling with Metabolic Adaptation in Lymphocytes

Project description:Interleukin (IL)-23 mediated signal transduction represents a major molecular mechanism underlying the pathology of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC). In addition, emerging evidence supports the role of IL-23-driven Th17 cells in inflammation. Components of the IL-23 signalling pathway, such as IL23R, JAK2 and STAT3, have been characterised, but elements unique to this network as compared to other interleukins have not been readily addressed. In this study, we have undertaken a multi-stage phosphoproteomics approach to better characterise downstream signalling events. To this end, we performed and compared phosphopeptide and phosphoprotein enrichment methodologies after activation of T lymphocytes by IL-23. We demonstrate the complementary nature of the two phosphor-enrichment approaches by maximising the capture of phosphorylation events. A total of 8069 unique phosphopeptides (containing 8344 unique sites), and 4317 unique phosphorylated proteins were identified, amongst which STAT3, PKM2, CDK6 and LASP-1 clearly showed induction of specific phosphorylation sites that were not readily observed after IL-2 stimulation. Interestingly, we observed subsequent translocation of STAT3 and PKM2 to the nucleus as well as increased phosphorylation especially of the nuclear portion at ~30 min after IL-23 stimulation, suggesting a wide range of cellular responses including proliferation and metabolic adaptation.

2016-04-21 | PXD002990 | Pride

An innate IL-25-ILC2-MDSC axis creates a cancer-permissive microenvironment for Apc-mutation-driven intestinal tumorigenesis

Project description:Interleukin-25 and group 2 innate lymphoid cells (ILC2s) defend the host against intestinal helminth infection, and are associated with inappropriate allergic reactions. Recently, it was reported that IL-33-activated ILC2s augment protective tissue-specific pancreatic cancer immunity. Here we show a diametrically opposite role for intestinal IL-25-activated ILC2s where they create an innate cancer-permissive microenvironment. Colorectal cancer (CRC) patients with higher tumor IL25 expression have reduced survival, and increased IL-25 Rexpressing tumor-resident ILC2s and myeloid-derived suppressor cells (MDSCs) associated with impaired anti-tumor responses. Ablation of IL-25-signalling reduced tumors, virtually doubling life-expectancy in an Apc-mutation-driven model of spontaneous intestinal tumorigenesis. Mechanistically, IL-25 promotes tumor ILC2s, which sustain MDSCs to suppress anti-tumor immunity. Therapeutic blockade of IL-25-signalling decreased ILC2s, MDSCs and adenoma/adenocarcinoma, while increasing anti-tumor IFNg and adaptive T cell immunity. Thus, the roles of innate epithelium-derived cytokines IL-25 and IL-33, and ILC2s in cancer cannot be generalized, and instead offer differential pathways for therapeutic intervention.

2022-04-20 | GSE199113 | GEO

IL-22 Prevents Epithelial Dysfunction During Citrobacter rodentium-induced Infectious Colitis

Project description:IBD is a complex autoimmune disease characterized by dysregulated interactions between host immune responses and microbiome at the intestinal epithelium interface. Here we identified shared protein alterations in intestinal epithelial differentiation and function between IBD and Citrobacter rodentium infected FVB mice. We discovered that prophylactic treatment with the mucosal healing therapy IL-22.Fc in the infected FVB mice reduced disease severity and rescued the mice from lethality. Notably, we observed an emergence of intermediate undifferentiated intestinal epithelial cells upon infection, with disrupted expression of the solute transporter machinery as well as components critical for intestinal barrier integrity. Multi-omics analyses revealed that with IL-22.Fc treatment several disease associated changes were prevented (including disruption of the solute transporter machinery), and proper physiological homeostatic functions of the intestine was restored. Taken together, we unveiled the disease relevance of the C. rodentium induced colitis model to IBD and demonstrated the protective role of the mucosal healing therapy IL-22.Fc in ameliorating the epithelial dysfunction.

2023-10-05 | PXD024688 | Pride

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