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Inactivation of mTORC2 in macrophages is a signature of colorectal cancer that promotes tumorigenesis.

ABSTRACT: Gene expression analysis of sorted colon macrophages of Rictor fl/fl LysM+/+ and Rictor fl/fl LysM+/cre mice Dysregulations of immune and metabolic processes can lead to chronic inflammation, which is one of the driving forces for the development of cancer. Macrophages are regulators of these processes and therefore have a fundamental role for the initiation of cancer. Here we find that deletion of Rictor in myeloid cells increases tumor number and size in the colitis-associated colorectal cancer model and leads to a stronger inflammatory response in the underlying acute DSS-colitis model. OPN is shown to be upregulated in the serum of myeloid-specific Rictor-KO mice during the DSS-colitis and the more severe phenotype, characterized by decreased survival, increased weight loss, shorter colons and enhanced infiltration of immune cells into the colon, can be reverted by the neutralization of OPN in these mice. Microarray analysis reveals a change in inflammatory and metabolic gene signatures of Rictor-KO colon macrophages that is also seen in the Rictor-KO BMDM in vitro. Therefore, our data show that myeloid Rictor controls macrophage polarization and the cellular energy metabolism, thereby suppressing colitis and colitis-associated colorectal cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE96525 | GEO | 2019/11/12

REPOSITORIES: GEO

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Expression data of lamina propria macrophages from LysMCre and LysMCre;Arntfl/fl mice with DSS-induced acute colitis

Project description:Mice with myeloid ARNT deficiency (LysMCre;Arntfl/fl mice) exhibit defective resolution of DSS-induced acute colitis compared to LysMCre mice. This microarray is carried out to compare the phenotype of lamina propria macrophages from the two cohorts, and to identify factors that are disrupted by myeloid ARNT deficiency and can potentially contribute to the defective resolution of acute colitis.

2018-11-12 | GSE121078 | GEO

RNA-seq of IL-4 complex treated tissue resident macrophages vs. monocytic macrophages from LysM Cre+ (WT litermate control) and LysM Cre+ RICTOR KO (myeloid specifically RICTOR deleted) mice

Project description:RNA-seq was performed on sorted peritoneal tissue resident macrophages (CD11b+F4/80hiTIM4+) and monocytic macrophages (CD11b+F4/80loTIM4-) from IL-4c (recombinant IL-4 (5µg) and anti-IL-4 ab (12.5µg) IP injection on days 0 and 2 and sorted on day 4) treated 6-8wks old LySM Cre+ and LysM Cre+ RICTOR KO (C57BL/6 background) for expression profiling

2017-10-01 | GSE94965 | GEO

USP2 promotes experimental colitis and bacterial infections by inhibiting the proliferation of myeloid cells and remodeling the extracellular matrix network

Project description:Inflammatory bowel disease (IBD) is closely associated with dysregulation of genetic factors and microbial environment. Here, we report a susceptible role of ubiquitin-specific protease 2 (USP2) in experimental colitis and bacterial infections. USP2 is upregulated in the inflamed mucosa of IBD patients and in the colon of mice treated with dextran sulfate sodium salt (DSS). Knockout or pharmacologic inhibition of USP2 promotes the proliferation of myeloid cells to activate IL-22 and IFNg production of T cells. In addition, knockout of USP2 in myeloid cells inhibits the production of pro-inflammatory cytokines to relieve the dysregulation of extracellular matrix (ECM) network and promote the gut epithelial integrity after DSS treatment. Consistently, Lyz2-Cre;Usp2fl/fl mice exhibit hyper-resistance to DSS-induced colitis and Citrobacter rodentium infections compared to Usp2fl/fl mice. These findings highlight an indispensable role of USP2 in myeloid cells to modulate T cell activation and epithelial ECM network and repair, indicating USP2 as a potential target for therapeutic intervention of IBD and bacterial infections in the gastrointestinal system.

2022-07-18 | GSE208325 | GEO

RNA-seq analysis of Mettl3fl/fl and LysM-cre, Mettl3fl/fl BMDMs (bone-marrow-derived macrophages) Transcriptomes

Project description:To comprehensively learn about the mechanisms of METTL3-mediated pro-tumoral functions, we performed RNA-sequencing to identify differentially expressed genes in bone-marrow-derived macrophages (BMDMs) in Mettl3fl/fl (WT) and LysM-cre, Mettl3fl/fl (KO) mice after co-cultured with MC38 cell line.

2022-01-01 | GSE182865 | GEO

TRIM33 deficiency in mature myeloid cells impairs resolution of colonic inflammation

Project description:Mature myeloid cells play a crucial role in the pathogenesis of Crohn disease (CD) but the molecular players that regulate their functions in CD are not fully characterized. Here we show that Trim33 mRNA level is decreased in CD patient’s blood monocytes and characterize TRIM33 functions in monocytes during dextran sulfate sodium (DSS) induced colitis. Mice deleted for trim33 only in mature myeloid cells (Trim33-/- mice) display an impaired resolution of colonic inflammation. This deficiency is associated with an increased number of blood and colon neutrophils and monocytes and a decreased number of colonic macrophages. In accordance, Trim33-/- monocytes are less competent that wild type monocytes for recruitment and differentiation into macrophages at the inflammatory site. Furthermore, during resolution of DSS-induced colitis, Trim33-/- colonic macrophages display an impaired M1/M2 switch and express a low level of membrane bound TNFα known to regulate resolution of inflammation. Altogether, these results show an important role of TRIM33 in monocytes/macrophages during the resolution of DSS-induced colonic inflammation and pinpoint TRIM33 as a novel Crohn disease biomarker and as a potential therapeutic target.

2019-07-26 | GSE124778 | GEO

Interleukin 17 B is protective in colitis by regulating colonic mononuclear phagocytes in mice [BMDM]

Project description:IL17B protected mice from dextran sodium sulfate (DSS)-induced colitis since IL17B deficiency resulted in severe DSS-induced colitis with exaggerated weight loss, shorter colon length, and elevated proinflammatory cytokine production in colon. For mechanism study, we use single cell transcriptional analyses of CD45+ immune cells in colonic lamina propria to detect the effect of IL-17B on colon LP immune cells in colitis. We found increased inflammatory macrophages infiltration in colon lamina propria after colitis induction expressing inflammatory cytokines such as S100a9, S100a8, Tnf, which was confirmed by real-time PCR and flow cytometry. Reconstitute of Il17b-/- mice with recombinant IL17B alleviated the severity of DSS-induced colitis. IL17B treatment also inhibited LPS-induced inflammation in bone marrow derived macrophage and in mice. These data indicate that IL17B exerting its inhibitory role in inflammation by regulating inflammatory macrophage response. In view of the protective effect of IL17B on DSS-induced colitis and LPS-induced inflammation, IL17B might represent a novel potential therapeutic approach to treat the inflammation.

2023-01-17 | GSE162062 | GEO

Interleukin 17 B is protective in colitis by regulating colonic mononuclear phagocytes in mice

2023-01-17 | GSE161987 | GEO

Mus musculus

Project description:RNA-seq of IL-4 complex treated tissue resident macrophages vs. monocytic macrophages from LysM Cre+ (WT litermate control) and LysM Cre+ RICTOR KO (myeloid specifically RICTOR deleted) mice

| PRJNA374962 | ENA

IL-4 stimulation of Dicer deficient bone-marrow derived macrophages in vitro

Project description:Macrophages were derived from the bone-marrow of 3 x fl/+ Dicer LysCre +/- (wild-type) and 3 x fl/fl Dicer LysCre +/- mice and stimulated with IL-4 (50ng/mL) for 72h. Total RNA was isolated and analyzed by gene array. In this experiment, we derived Dicer deficient bone-marrow macrophages using Dicer fl/+ LysM-Cre by Dicer fl/+ crossed mice to obtain Dicer fl/fl LysM-cre progeny (and Dicer deficient macrophages). Next, we studied the effects of IL-4 stimulation in macrophage with a deficiency in Dicer/microRNAs.

2012-03-17 | E-GEOD-36585 | biostudies-arrayexpress

mRNA transcriptome sequencing of wild type (WT) and intestinal epithelial cell specific Axin1 Knockout mice (Axin1KOΔIEC) that have udergone DSS-induced colitis and AOM/DSS-induced colorectal tumorigenesis

Project description:Purpose : The goals of this study are to compare NGS-derived transcriptome profiling (RNA-seq) of colon samples of intestinal epithelial cell specific Axin1 Knockout mice and WT controls that were submitted to DSS-induced colitis and AOM/DSS-induced colorectal carcinogenesis. Methods : DSS-induced colitis was performed on Axin1flfl (WT) and Vil CreERT2;Axin1fl/fl (Axin1KOΔIEC) mice by giving 3% DSS dissolved in drinking water for 7 days and subsequently placed on regular water for recovery before sacrifice at Day 7 and D13. Methods : AOM/DSS-induced colorectal tumorigenesis was performed on Axin1flfl (WT) and Vil CreERT2;Axin1fl/fl (Axin1KOΔIEC) mice that were sacrificed at day 100 post-AOM injection to collect colorectal tumors. Methods : Colonic mRNA profiles of WT and Axin1KOΔIEC mice were generated by deep sequencing using Illumina NextSeq 500 instrument (150base-lengths read V2 chemistry in a paired-end mode)

2022-02-09 | GSE196220 | GEO

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