Myeloid-stromal subtypes reveal NOD2-mediated Crohn's and rescue pathways
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA632595 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11785621.fastq.gz | Fastqsanger.gz | |||
| SRR11785622.fastq.gz | Fastqsanger.gz | |||
| SRR11785623.fastq.gz | Fastqsanger.gz | |||
| SRR11785624.fastq.gz | Fastqsanger.gz | |||
| SRR11785625.fastq.gz | Fastqsanger.gz |
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Project description:Crohn’s disease (CD) is a chronic inflammatory intestinal disease, often characterized by aberrant healing and stricturing complications. Mechanisms underlying NOD2-pathogenicity and salvage pathways in anti-TNF and refractory patients remain largely uncharacterized. Here we show that loss of NOD2 function leads to aberrant activated fibroblast and macrophage homeostasis through the upregulation of a pathogenic signature, and propose new precision therapeutic approaches involving gp130 blockade for select CD patients, to potentially supplement anti-TNF therapy
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Project description:Crohn's disease is a chronic inflammatory intestinal disease that is frequently accompanied by aberrant healing and stricturing complications. Crosstalk between activated myeloid and stromal cells is critical in the pathogenicity of Crohn's disease1,2, and increases in intravasating monocytes are correlated with a lack of response to anti-TNF treatment3. The risk alleles with the highest effect on Crohn's disease are loss-of-function mutations in NOD24,5, which increase the risk of stricturing6. However, the mechanisms that underlie pathogenicity driven by NOD2 mutations and the pathways that might rescue a lack of response to anti-TNF treatment remain largely uncharacterized. Here we use direct ex vivo analyses of patients who carry risk alleles of NOD2 to show that loss of NOD2 leads to dysregulated homeostasis of activated fibroblasts and macrophages. CD14+ peripheral blood mononuclear cells from carriers of NOD2 risk alleles produce cells that express high levels of collagen, and elevation of conserved signatures is observed in nod2-deficient zebrafish models of intestinal injury. The enrichment of STAT3 regulation and gp130 ligands in activated fibroblasts and macrophages suggested that gp130 blockade might rescue the activated program in NOD2-deficient cells. We show that post-treatment induction of the STAT3 pathway is correlated with a lack of response to anti-TNF treatment in patients, and demonstrate in vivo in zebrafish the amelioration of the activated myeloid-stromal niche using the specific gp130 inhibitor bazedoxifene. Our results provide insights into NOD2-driven fibrosis in Crohn's disease, and suggest that gp130 blockade may benefit some patients with Crohn's disease-potentially as a complement to anti-TNF therapy.
| S-EPMC8284870 | biostudies-literature
Project description:Short title: Innate Gene/miRNA MDP-response in CD RNA-seq and small RNA-seq were used to identify the expression of gene and microRNA (miRNA) in monocytes from healthy controls and patients with Crohn's Disease (CD), with and without NOD2 (nucleotide-binding oligomerization domain-containing protein 2) single nucleotide polymorphisms (SNPs) after stimulation with muramyl dipeptide (MDP).
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Project description:RIPK2 mediates inflammatory signaling by the bacteria-sensing receptors NOD1 and NOD2, and inhibition of RIPK2 by kinase inhibitors is an emerging strategy to ameliorate NOD-mediated pathologies. However, the role for RIPK2’s kinase activity remains unclear. Here, we reveal that RIPK2 kinase activity is dispensable for NOD2 inflammatory signaling and show that RIPK2 inhibitors function instead by antagonizing XIAP-binding and XIAP-mediated ubiquitination of RIPK2. We map the XIAP binding site on RIPK2 to the loop between 2 and 3 of the N-lobe of the kinase, which is in close proximity to the ATP-binding pocket. Through characterization of a new series of ATP-competitive RIPK2 inhibitors, we identify the molecular features that determine their inhibition of both the RIPK2-XIAP interaction, and of cellular and in vivo NOD2 signaling. Our study exemplifies how targeting of the ATP-binding pocket in RIPK2 can be exploited to interfere with the RIPK2-XIAP interaction for modulation of NOD signaling.
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Project description:NOD2 is an intracellular receptor for the bacterial cell wall component muramyl dipeptide (MDP) and variants of NOD2 are associated with chronic inflammatory diseases of barrier organs e.g. Crohn disease, asthma and atopic eczema. It is known that activation of NOD2 induces a variety of inflammatory and antibacterial factors. The exact transcriptomal signatures that define the cellular programs downstream of NOD2 activation and the influence of the Crohn-associated variant L1007fsinsC are yet to be defined. To describe the MDP-induced activation program, we analyzed the transcriptomal reactions of isogenic HEK293 cells expressing NOD2wt or NOD2L1007fsinsC to stimulation with MDP. Importantly, a clear loss-of-function could be observed in the cells carrying the Crohn-associated variant L1007fsinsC, while the NOD2wt cells showed differential regulation of growth factors, chemokines and several antagonists of NF-κB, e.g. TNFAIP3 (A20) and IER3.
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Project description:Instability in the composition of gut bacterial communities, referred as dysbiosis, has been associated with important human intestinal disorders such as Crohn’s disease and colorectal cancer. Our data showed that Nod2-mediated risk of intestinal inflammation in colitis model is communicable to WT mice by cohousing. Here, we investigated if Nod2-deficient mice microbiota is able to change transcript profiles in Nod2-immunocompetent mice (C57Bl6/J mice) independently of colitis.
2013-01-02 | GSE36481 | GEO
Project description:NOD2 is an intracellular receptor for the bacterial cell wall component muramyl dipeptide (MDP) and variants of NOD2 are associated with chronic inflammatory diseases of barrier organs e.g. Crohn disease, asthma and atopic eczema. It is known that activation of NOD2 induces a variety of inflammatory and antibacterial factors. The exact transcriptomal signatures that define the cellular programs downstream of NOD2 activation and the influence of the Crohn-associated variant L1007fsinsC are yet to be defined. To describe the MDP-induced activation program, we analyzed the transcriptomal reactions of isogenic HEK293 cells expressing NOD2wt or NOD2L1007fsinsC to stimulation with MDP. Importantly, a clear loss-of-function could be observed in the cells carrying the Crohn-associated variant L1007fsinsC, while the NOD2wt cells showed differential regulation of growth factors, chemokines and several antagonists of NF-κB, e.g. TNFAIP3 (A20) and IER3. To elucidate the MDP-induced activation program we generated isogenic HEK293 cells stably expressing wildtype NOD2 or NOD2L1007fsinsC using a FRT-recombinase based approach. Cells carrying the inserted vector cassette were used as controls (mock-transfectant). To comprehensively analyze NOD2-mediated innate immune responses we analyzed transcriptomal signature patterns using genome-wide cDNA microarrays. Samples were harvested from cell cultures under normal growth conditions 0 h, 2 h and 6 h after MDP‑ stimulation of the cells.
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Project description:Profiling of ileal mucosal gene expression in Chron's disease patients with and without NOD2 risk alleles; through microarray analyses it was discovered that 18 genes related to lymphocyte and phagocyte activation recuitment were upregulated in affected ileum in NOD2R patients as compared to ileum in NOD2s (no risk alleles) patients, thus supporting the concept that NOD2 risk alleles contribute to impaired regulation of inflammation in the ileum.
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Project description:Instability in the composition of gut bacterial communities, referred as dysbiosis, has been associated with important human intestinal disorders such as CrohnM-bM-^@M-^Ys disease and colorectal cancer. Here, we show that dysbiosis coupled to Nod2 or Rip2 deficiency suffices to cause an increased risk for intestinal inflammation and colitis-associated carcinogenesis in mice. Aggravated epithelial lesions and dysplasia upon chemical-induced injury associated with loss of Nod2 or Rip2 can be prevented by antibiotics or anti-IL6R treatment. Nod2-mediated risk for intestinal inflammation and colitis-associated tumorigenesis is communicable through maternally-transmitted microbiota even to wild-type hosts. Disease progression was identified to drive complex NOD2-dependent changes of the colonic-associated microbiota. Reciprocal microbiota transplantation rescues the vulnerability of Nod2-deficient mice to colonic injury. Altogether, our results unveil an unexpected function for NOD2 in shaping a protective assembly of gut microbial communities, providing a rationale for intentional manipulation of genotype-dependent dysbiosis as a causative therapeutic principle in chronic intestinal inflammation. Analysis used RNA extracted from colonic mucosa of untreated, antibiotics-treated or metronidazole-treated C57Bl/6J and Nod2-deficient mice in CAC model. Direct comparisons were performed as follow: C57Bl/6J untreated mice vs Nod2-deficient untreated mice, C57Bl/6J antibiotics-treated mice vs Nod2-deficient antibiotics-treated mice, C57Bl/6J metronidazole-treated mice vs Nod2-deficient metronidazole-treated mice, C57Bl/6J untreated mice vs C57Bl/6J antibiotics-treated mice, C57Bl/6J untreated mice vs C57Bl/6J metronidazole-treated mice, Nod2-deficient untreated mice vs Nod2-deficient antibiotics-treated mice, Nod2-deficient untreated mice vs Nod2-deficient metronidazole-treated mice. Indirect comparisons with control data were made across multiple arrays with raw data pulled from different channels for data analysis.
2013-01-02 | E-GEOD-32421 | biostudies-arrayexpress