Interleukin 22 mediates interleukin 23-induced pathology in newborn mice by disrupting the function of pancreatic and intestinal cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA565398 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10116206.fastq.gz | Fastqsanger.gz | |||
| SRR10116207.fastq.gz | Fastqsanger.gz | |||
| SRR10116208.fastq.gz | Fastqsanger.gz | |||
| SRR10116209.fastq.gz | Fastqsanger.gz | |||
| SRR10116210.fastq.gz | Fastqsanger.gz |
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Project description:This SuperSeries is composed of the SubSeries listed below.
2019-09-14 | GSE137415 | GEO
Project description:Interleukin-23 (IL-23) is a pro-inflammatory cytokine required for the pathogenicity of T helper 17 (Th17) cells but the molecular mechanisms governing this process remain unclear. We identified the transcription factor Blimp-1 (Prdm1) as a key IL-23-induced factor that drove the inflammatory function of Th17 cells. In contrast to thymic deletion of Blimp-1, which causes T cell development defects and spontaneous autoimmunity, peripheral deletion of this transcription factor resulted in reduced Th17 activation and reduced severity of autoimmune encephalomyelitis. Furthermore, genome wide occupancy and overexpression studies in Th17 cells revealed that Blimp-1 co-localized with transcription factors RORγt, STAT-3 and p300 at the Il23r, Il17a/f and Csf2 cytokine loci to enhance their expression. Blimp-1 also directly bound to and repressed cytokine loci Il2 and Bcl6. Taken together, our results demonstrate that Blimp-1 is an essential transcription factor downstream of IL-23 that acts in concert with RORγt to activate the Th17 inflammatory program. Genome-wide binding analysis of Blimp1 from in vitro generated T effector and regulatory cells
2016-06-15 | E-GEOD-75724 | biostudies-arrayexpress
Project description:Interleukin-23 (IL-23) is a pro-inflammatory cytokine required for the pathogenicity of T helper 17 (Th17) cells but the molecular mechanisms governing this process remain unclear. We identified the transcription factor Blimp-1 (Prdm1) as a key IL-23-induced factor that drove the inflammatory function of Th17 cells. In contrast to thymic deletion of Blimp-1, which causes T cell development defects and spontaneous autoimmunity, peripheral deletion of this transcription factor resulted in reduced Th17 activation and reduced severity of autoimmune encephalomyelitis. Furthermore, genome wide occupancy and overexpression studies in Th17 cells revealed that Blimp-1 co-localized with transcription factors RORγt, STAT-3 and p300 at the Il23r, Il17a/f and Csf2 cytokine loci to enhance their expression. Blimp-1 also directly bound to and repressed cytokine loci Il2 and Bcl6. Taken together, our results demonstrate that Blimp-1 is an essential transcription factor downstream of IL-23 that acts in concert with RORγt to activate the Th17 inflammatory program.
2016-06-15 | GSE75724 | GEO
Project description:Interleukin 23 (IL-23) triggers pathogenic features in pro-inflammatory, IL-17-secreting T cells (Th17 and Tγδ17) that play a key role in the development of inflammatory diseases. However, the IL-23 signaling cascade remains largely undefined. Here we used quantitative phosphoproteomics to characterize IL-23 signaling in primary murine Th17 cells. We quantified 6,888 phosphorylation sites in Th17 cells, and found 168 phosphorylations regulated upom IL-23 stimulation. IL-23 increased the phosphorylation of the myosin regulatory light chain (RLC), an actomyosin contractibility marker, in Th17 and Tγδ cells. IL-23-induced RLC phosphorylation required JAK2 and ROCK catalytic activity, and the study of the IL-23/ROCK axis revealed an unexpected role of IL-23 in the migration of Tγδ17 and Th17 cells. Moreover, pharmacological inhibition of ROCK reduced Tγδ17 recruitment to inflamed skin upon challenge with inflammatory agent Imiquimod. This work: i) provides new insights into phosphorylation networks that control Th17 cells, ii) widely expands the current knowledge on IL-23 signaling, and iii) contributes to the increasing list of immune cells subsets characterized by global phosphoproteomic approaches.
2020-03-25 | PXD016633 | Pride
Project description:The key role of interleukin (IL)-23 in the pathogenesis of autoimmune and chronic inflammatory disorders is supported by the identification of IL-23 receptor (IL-23R) susceptibility alleles associated with inflammatory bowel disease, psoriasis and ankylosing spondylitis. IL-23-driven inflammation has primarily been linked to the actions of T-helper type 17 (TH17) cells. Somewhat overlooked, IL-23 also has inflammatory effects on innate immune cells and can drive T-cell-independent colitis. However, the downstream cellular and molecular pathways involved in this innate intestinal inflammatory response are poorly characterized. Here we show that bacteria-driven innate colitis is associated with an increased production of IL-17 and interferon-gamma in the colon. Stimulation of colonic leukocytes with IL-23 induced the production of IL-17 and interferon-gamma exclusively by innate lymphoid cells expressing Thy1, stem cell antigen 1 (SCA-1), retinoic-acid-related orphan receptor (ROR)-gammat and IL-23R, and these cells markedly accumulated in the inflamed colon. IL-23-responsive innate intestinal cells are also a feature of T-cell-dependent models of colitis. The transcription factor ROR-gammat, which controls IL-23R expression, has a functional role, because Rag-/-Rorc-/- mice failed to develop innate colitis. Last, depletion of Thy1+ innate lymphoid cells completely abrogated acute and chronic innate colitis. These results identify a previously unrecognized IL-23-responsive innate lymphoid population that mediates intestinal immune pathology and may therefore represent a target in inflammatory bowel disease.
| S-EPMC3796764 | biostudies-literature
Project description:The pro-inflammatory cytokine interleukin-23 (IL-23) has been implicated in colorectal carcinogenesis (CRC). Yet, the cell-specific contributions of IL-23 receptor (IL-23R) signaling in CRC remain unknown. One of the cell types that highly expresses IL-23R are colonic regulatory T cells (Treg cells). The aim of this study was to define the contribution of Treg cell-specific IL-23R signaling in sporadic and inflammation-associated CRC. In mice, the role of IL-23R in Treg cells in colitis-associated cancer (CAC) was investigated using azoxymethane/dextran sodium sulphate in wild-type Treg cell reporter mice (WT, Foxp3YFP-Cre), and mice harboring a Treg cell-specific deletion of IL-23 (Il23rΔTreg). Il23rΔTreg mice had increased dysplasia compared to WT mice associated with decreased tumor-infiltrating macrophages. The role of Treg cell IL-23R in sporadic CRC was examined via orthotopic injection of the syngeneic colon cancer cell line MC-38 submucosally into the colon/rectum of mice. In the sporadic cancer model, Il23rΔTreg mice had increased survival and decreased tumor size compared to WT mice. Additionally, MC-38 tumors of Il23rΔTreg mice had a higher frequency of pro-inflammatory macrophages and IL-17 producing CD4+ T cells. This data suggests that loss of IL-23R signaling in Treg cells permits IL-17 production by CD4+ T cells that in turn promotes pro-inflammatory macrophages to clear tumors. These findings further support and highlight the importance of selecting a physiologically relevant model based on the type of cancer in which to evaluate the role of specific genes in late tumorigenesis. Finally, single-cell RNA-seq analysis of a previously published dataset in human sporadic cancer, revealed that IL23R was highly expressed in CRC compared to other cancers and specifically in tumor-associated Treg cells.
2024-02-28 | GSE240707 | GEO
Project description:Neonatal inflammatory diseases are associated with severe morbidity, but the inflammatory factors underlying them and their potential effector mechanisms are poorly defined. Here we show that necrotizing enterocolitis in neonate mice is accompanied by elevation of IL-23 and IL-22 and decreased production of pancreatic enzymes. These phenotypes are mirrored in neonate mice overexpressing IL-23 in CX3CR1+ myeloid cells or in keratinocytes. The mice fail to grow and die prematurely, displaying systemic inflammation, nutrient malabsorption and decreased expression of intestinal and pancreatic genes mediating digestion and absorption of carbohydrates, proteins, and lipids. Germ-free environment improves, and genetic ablation of IL-22 restores normal growth in mice overexpressing IL-23. Mechanistically, IL-22 acts directly at the level of pancreatic acinar cells to decrease expression of the pancreas associated transcription factor 1a (PTF1a). These results show that augmented production of IL-23 and IL-22 in early life has a negative impact on pancreatic enzyme secretion and food absorption.
| S-EPMC6778080 | biostudies-other
Project description:In Alzheimer’s disease (AD), sensome receptor dysfunction impairs microglial danger-associated molecular pattern (DAMP) clearance and exacerbates disease pathology. While extrinsic signals including interleukin-33 (IL-33) can restore microglial DAMP clearance, it remains largely unclear how the sensome receptor(s) is regulated and interacts with DAMP during phagocytic clearance. Here, we show that IL-33 induces VCAM1 in microglia, which promotes microglial chemotaxis toward amyloid-beta (Aβ) plaque-associated ApoE, and leads to Aβ clearance. We show that IL-33 stimulates a chemotactic state in microglia, characterized by Aβ-directed migration. Functional screening identified that VCAM1 directs microglial Aβ chemotaxis by sensing Aβ plaque-associated ApoE. Moreover, we found that disrupting VCAM1–ApoE interaction abolishes microglial Aβ chemotaxis, resulting in decreased microglial clearance of Aβ. In patients with AD, higher cerebrospinal fluid levels of soluble VCAM1 were correlated with impaired microglial Aβ chemotaxis. Together, our findings demonstrate that promoting VCAM1–ApoE-dependent microglial functions ameliorates AD pathology.
2023-07-18 | GSE208006 | GEO
Project description:Rationale: Throughout the years, there has been a rapid change in the perioperative protocols and procedures surrounding colorectal surgery. Upon the introduction of the Enhanced Recovery After Surgery (ERAS) program in Western countries, an improvement in postoperative outcomes was seen. Nowadays, researchers focus on further improving the current standard ERAS programs enabling an accelerated version hereof.
Objective: The aim of this study is to investigate the feasibility and safety of a 23-hour accelerated ERAS protocol (ERAS 2.0) for patients undergoing colorectal surgery compared to a retrospective cohort of patients who followed ERAS 1.0 for colorectal surgery. In this ERAS 2.0 protocol, patients undergoing colorectal surgery will be discharged within 23 hours after surgery.
Study design: This study is an investigator-initiated, single-center prospective study.
Study population: Patients aged ≥ 18 years ≤ 80 undergoing surgical resection for colorectal pathology that meet the eligibility criteria will be invited to participate in this study.
Intervention: Adhering to a strict multidisciplinary and multifaceted ERAS 2.0 protocol, patients receiving elective colorectal surgery will be discharged 23-hours after surgery.
Main study parameters/endpoints: Rate of the successful and safe application of the 23-hour accelerated ERAS 2.0 protocol for patients undergoing elective colorectal surgery. Success rate will be measured in readmission rate and safety will be measured with rate of serious adverse events (Clavien Dindo ≥3b). Success rate (feasibility) will also be measured in percentage of patients who were not able to be discharged 23 hours after surgery.
| 2344831 | ecrin-mdr-crc
Project description:Sulforaphane (SFN), an isothiocyanate, is part of an important group of naturally occurring small molecules with antiinflammatory properties. Even though the published reports are vague, most are best conceivable with an inhibition of T cell functions. We therefore analyzed the effect of SFN on T cell-mediated autoimmune disease. Feeding mice with SFN protected from severe experimental autoimmune encephalomyelitis (EAE). Disease amelioration was associated with reduced interleukin (IL)-17 and IFN-gamma expression in draining lymph nodes. In vitro, SFN treatment of T cells did not directly alter T cell cytokine secretion. In contrast, SFN treatment of dendritic cells (DC) inhibited TLR4-induced IL-12 and IL-23 production and the cytokine profile of T cells stimulated by SFN-treated DC. SFN suppressed TLR4-induced nuclear factor kappa B (NFκB) activity, without affecting the degradation of its inhibitor (IκB). Instead, SFN treatment of DC resulted in strong expression of the stress response protein heme oxygenase-1 (HO-1), which interacts with NFκB p65 and inhibits its activity. Consistent with these findings, HO-1 bound to p65 and subsequently inhibited the p65 promoter activity within the IL23a and IL12b promoter region. Importantly, SFN suppressed Il23a and Il12b expression in vivo and silenced Th17/Th1 responses within the CNS . Our data show that SFN improves Th17/Th1-mediated autoimmune disease by inducing HO-1 and inhibiting p65-regulated IL-23 and IL-12 expression. Treatment-control experiment with two replicates per condition
2014-02-13 | E-GEOD-54980 | biostudies-arrayexpress