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Glucocorticoid induced gene-regulation in murine bone marrow derived monocytes.

ABSTRACT: Glucocorticoids (GC) are used as first line therapies for generalized suppression of inflammation (e.g. allergies or autoimmune diseases), but their long-term use is limited by severe side effects. Our previous work has revealed that GC induced a stable anti-inflammatory phenotype in monocytes, the glucocorticoid-stimulated monocytes (GCsM) that we now exploited for targeted GC-mediated therapeutic effects. We demonstrate that GCsM interact with T-cells in suppressing proliferation as well as cytokine release of CD8+ and especially CD4+ T-cells in vitro, and that they support generation of Foxp3+ cells. We therefore tested their immunosuppressive potential in CD4+ T-cell-induced colitis in vivo. We found that injection of GCsM into mice with already established severe colitis abolishes the inflammation and results in significant clinical improvement within a few days. T-cells recovered from GCsM-treated mice reveal reduced secretion of pro-inflammatory cytokines IFN- or IL-17. Furthermore, accumulation of clusters of Foxp3+ CD4+ T-cells were detectable at local sites of inflammation in their colon. Thus, GCsM are able to modify T-cell responses in vitro and in vivo and are able to down-regulate and clinically cure an established severe T-cell mediated colitis.

ORGANISM(S): Mus musculus

PROVIDER: GSE54778 | GEO | 2014/09/02

SECONDARY ACCESSION(S): PRJNA237608

REPOSITORIES: GEO

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Glucocorticoid induced gene-regulation in murine bone marrow derived monocytes.

Project description:Glucocorticoids (GC) are used as first line therapies for generalized suppression of inflammation (e.g. allergies or autoimmune diseases), but their long-term use is limited by severe side effects. Our previous work has revealed that GC induced a stable anti-inflammatory phenotype in monocytes, the glucocorticoid-stimulated monocytes (GCsM) that we now exploited for targeted GC-mediated therapeutic effects. We demonstrate that GCsM interact with T-cells in suppressing proliferation as well as cytokine release of CD8+ and especially CD4+ T-cells in vitro, and that they support generation of Foxp3+ cells. We therefore tested their immunosuppressive potential in CD4+ T-cell-induced colitis in vivo. We found that injection of GCsM into mice with already established severe colitis abolishes the inflammation and results in significant clinical improvement within a few days. T-cells recovered from GCsM-treated mice reveal reduced secretion of pro-inflammatory cytokines IFN-M-oM-^AM-' or IL-17. Furthermore, accumulation of clusters of Foxp3+ CD4+ T-cells were detectable at local sites of inflammation in their colon. Thus, GCsM are able to modify T-cell responses in vitro and in vivo and are able to down-regulate and clinically cure an established severe T-cell mediated colitis. Bone marrow derived monocytes where cultured 16 h with media containing M-CSF (control monocytes) or media containing M-CSF and dexamethasone (GCsM). In three independent experiments, total RNA from GCsM and control monocytes was isolated and processed for microarray hybridization.

2014-09-02 | E-GEOD-54778 | biostudies-arrayexpress

Quantitative proteomic Analysis Reveals up-regulation of caveolin-1 in FOXP3-overexpressed human gastric cancer cells

Project description:Forkhead box protein 3 (FOXP3) is implicated in tumor progression and prognosis in various types of tumor cells. We have recently reported that FOXP3 inhibited proliferation of gastric cancer (GC) cells through activating the apoptotic signaling pathway. In this study, we found that over-expression of FOXP3 inhibited GC cell migration, invasion and proliferation. Then, the label-free quantitative proteomic approach was employed to further investigating the down-stream proteins regulated by FOXP3, resulting in a total of 3,978 proteins quantified, including 186 significantly changed proteins. Caveolin-1 (CAV1), as a main constituent protein of caveolae, was one of those changed proteins up-regulated in FOXP3-overexpressed GC cells, moreover, it was assigned as one of the node proteins in the protein-protein interaction network and the key protein involved in focal adhesion pathway by bioinformatics analysis. Further biological experiments confirmed that FOXP3 directly bound to the promoter regions of CAV1 to positively regulate CAV1 transcription in GC cells. In summary, our study suggested that FOXP3 can be considered as a tumor suppressor in GC via positively regulating CAV1 through transcriptional activation, and this FOXP3-CAV1 transcriptional regulation axis may play an important role in inhibiting invasion and metastasis of GC cells.

2017-11-03 | PXD007725 | Pride

Lysophosphatidylserines derived from microbiota in Crohn’s disease elicit pathological Th1 response

Project description:Microbiota alteration and IFN-γ-producing CD4+ T cell overactivation are implicated in Crohn's disease (CD) pathogenesis. However, it remains unclear how dysbiosis enhances Th1 responses, leading to intestinal inflammation. Here, we identified key metabolites that are derived from dysbiotic microbiota and induce enhanced Th1 responses and severe colitis in mouse models. Patients with CD showed elevated lysophosphatidylserine (LysoPS) concentration in their feces, accompanied with a higher relative abundance of microbiota possessing a gene encoding the phospholipid-hydrolyzing enzyme phospholipase A. LysoPS induced metabolic reprograming, thereby eliciting aberrant effector responses in both human and mouse IFN-?-producing CD4+ T cells. Administration of LysoPS into T cell-dependent mouse colitis models induced severe inflammation. LysoPS-induced aggravation of colitis was impaired in mice lacking P2ry10 and P2ry10b, and their CD4+ T cells were hypo-responsive to LysoPS. Thus, our findings elaborate on the mechanism by which metabolites elevated in patients with CD harboring dysbiotic microbiota induce intestinal pathology.

2022-05-03 | GSE169006 | GEO

Immunoregulatory actions of T cell PPAR g at the colonic mucosa

Project description:BACKGROUND: Peroxisome proliferator-activated receptor g (PPAR g) is a nuclear receptor whose activation has been shown to modulate macrophage and epithelial cell-mediated inflammation. The objective of this study was to use a systems approach for investigating the mechanism by which the deletion of PPAR g in T cells modulates the severity of dextran-sodium sulfate (DSS)-induced colitis, immune cell distribution and global gene expression. METHODS: Wild-type (WT) or PPAR g flfl; CD4 Cre+ (CD4cre) mice in a C57BL/6 background were challenged with 2.5% DSS in their drinking water for 0, 2, or 7 days. Mice were scored on disease severity both clinically and histopathologically. Flow cytometry was used to assess lymphocyte and macrophage populations in the blood, spleen, and mesenteric lymph nodes (MLN). Global gene expression in colonic mucosa was profiled using Affymetrix microarrays. RESULTS: Both disease severity and inflammation-related body weight loss were accelerated by the deficiency of PPAR g in T cells. Examination of colon histopathology revealed significantly greater epithelial erosion, leukocyte infiltration, and mucosal thickening in the CD4cre mice on day 7. CD4cre mice had more CD8+ T cells than wt mice and fewer CD4+FoxP3+ regulatory T cells (Treg) and IL10+CD4+ T cells in blood and MLN, respectively. Transcriptomic profiling revealed around 3000 genes being transcriptionally altered as a result of DSS challenge in CD4cre mice. These included up-regulated adhesion molecules on day 7 and proinflammatory cytokines interleukin-6 (IL-6) and IL-1b, and suppressor of cytokine signaling 3 (SOCS-3) mRNA expression. CONCLUSIONS: These findings suggest that T cell PPAR g down-regulates inflammation during DSS colitis by inhibiting colonic expression of inflammatory mediators and increasing MLN Treg. Colonic mucosa from wt and CD4cre mice were sampled at 0 (no DSS), 2, and 7 days of DSS-induced experimental colitis

2010-07-08 | E-GEOD-20523 | biostudies-arrayexpress

RORα is critical for mTORC1 activity in T cell-mediated colitis [RNA-seq]

Project description:Inflammatory bowel disease (IBD) is multi-factorial chronic intestinal inflammation driven by pathogenic T cells. The mechanisms underlying colitis pathogenicity and anti-TNF therapy resistance are not fully understood. Here we demonstrate that RORα is highly expressed in active UC patients, particularly in those non-responsive to anti-TNF treatment. Rorα deficient CD4+ T cells could not induce severe gut inflammation in a T cell transfer colitis model. Mechanistically, RORα regulated T cell infiltration in colon by promoting T cell migration and inhibiting T cell apoptosis. Meanwhile, genome-wide occupancy and transcriptome analysis revealed that RORα promoted mTORC1 activation. mTORC1 signaling, also hyperactivated in active UC patients, was necessary for T cell-mediated colitis.

2021-07-28 | GSE168216 | GEO

RORα is critical for mTORC1 activity in T cell-mediated colitis [16S rRNA-seq]

2021-07-28 | GSE168218 | GEO

RORα is critical for mTORC1 activity in T cell-mediated colitis [ChIP-seq]

2021-07-28 | GSE168217 | GEO

Transcriptome analysis of Foxp3- CD25- regulatory T cells

Project description:The concept of immune regulation/suppression has been well-established. With thymus-derived CD4 CD25 regulatory T (TR) cells, it became clear that a variety of additional peripherally induced TR cells play vital roles in protection from many harmful immune responses including intestinal inflammation. In the present study, we have analyzed in vivo-induced Ag-specific CD4 TR cells with respect to their molecular and functional phenotype. By comparative genomics we could show that these Ag-specific TR cells induced by chronic Ag stimulation in vivo clearly differ in their genetic program from naturally occurring thymus-derived CD4 CD25 TR cells. This distinct population of induced TR cells express neither CD25 nor the TR-associated transcription factor Foxp3. Strikingly, CD25 is not even up-regulated upon stimulation. Despite the lack in Foxp3 expression, these in vivo-induced CD25 TR cells are able to interfere with an Ag-specific CD8 T cell-mediated intestinal inflammation without significant increase in CD25 and Foxp3 expression. Thus, our results demonstrate that in vivo-induced Ag-specific TR cells represent a distinct population of Foxp3 CD25 TR cells with regulatory capacity both in vitro and in vivo. Keywords: cell type comparison

2008-08-21 | GSE12506 | GEO

Transcription profiling of mouse Foxp3- CD25- regulatory T cells

2008-10-25 | E-GEOD-12506 | biostudies-arrayexpress

Vitamin D regulates the microbiota to induce RORgt/FoxP3+ regulatory T cells

Project description:The active form of vitamin D (1,25(OH)2D) suppresses experimental models of inflammatory bowel disease in part by regulating the microbiota. In this study, the role of vitamin D in the regulation of microbe induced RORgt/FoxP3+ T regulatory (reg) cells in the colon was determined. Vitamin D sufficient (D+) mice had significantly higher frequencies of FoxP3+ and RORgt/FoxP3+ T reg cells in the colon compared to vitamin D deficient (D-) mice. The higher frequency of RORgt/FoxP3+ T reg cells in D+ colon correlated with higher numbers of bacteria from the Clostridium XIVa and Bacteroides in D+ compared to D- cecum. D- mice with fewer RORgt/FoxP3+ T reg cells were significantly more susceptible to colitis than D+ mice. Transfer of the cecal bacteria from D+ or D- mice to germfree recipients phenocopied the higher numbers of RORgt/FoxP3+ cells and reduced susceptibility to colitis in D+ versus D- recipient mice. 1,25(OH)2D treatment of the D- mice beginning at 3 weeks of age did not completely recover RORgt/FoxP3+ T reg cells or the Bacteriodes, Bacteriodes thetaiotaomicron, and Clostridium XIVa numbers to D+ values. Early vitamin D status shapes the microbiota to optimize the population of colonic RORgt/FoxP3+ T reg cells important for resistance to colitis.

2019-07-17 | ST001219 | MetabolomicsWorkbench

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