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TRIM33 deficiency in mature myeloid cells impairs resolution of colonic inflammation

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE124778 | GEO | 2019/07/26

REPOSITORIES: GEO

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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

Global genome expression analysis of lamina propria derived WT and Nlrp6-/- Ly6C-hi inflammatory monocytes

Project description:Nlrp6-/- lamina propria Ly6C-hi monocytes in response to AOM/DSS have deficient TNFÎ± production, but increased production of other pro-inflammatory cytokines as compared to WT NLRP6 is a member of the Nod-like receptor family, whose members are involved in the recognition of microbes and/or tissue injury. NLRP6 was previously demonstrated to regulate the production of IL-18 and is important for protecting mice against chemically-induced intestinal injury and colitis-associated colon cancer. However, the cellular mechanisms by which NLRP6 reduces susceptibility to colonic inflammation remain unclear. Here, we determined that NLRP6 expression is specifically upregulated in Ly6Chi inflammatory monocytes that infiltrate into the colon during dextran sulfate sodium (DSS)-induced inflammation. Adoptive transfer of WT Ly6Chi inflammatory monocytes into Nlrp6-/- mice was sufficient to protect them from mortality, significantly reducing intestinal permeability and damage. NLRP6-deficient inflammatory monocytes were specifically defective in TNFÎ± production, which was important for reducing DSS-induced mortality and dependent on autocrine IL-18 signaling by inflammatory monocytes. Our data reveal a previously unappreciated role for NLRP6 in inflammatory monocytes, which are recruited during intestinal injury to promote barrier function and limit bacteria-driven inflammation. This study also highlights the importance of early cytokine responses, particularly NLRP6-dependent and IL-18-dependent TNFÎ± production in preventing chronic dysregulated inflammation. Ly6Chi monocytes were sorted from lamina propria of WT or Nlrp6-/- mice at day 10 of AOM/2%DSS. RNA was extracted and hybridized to the mouse 2.1 ST array.

2016-03-27 | E-GEOD-79631 | biostudies-arrayexpress

Immunoregulatory actions of epithelial cell PPAR g at the colonic mucosa

2010-07-08 | E-GEOD-20621 | biostudies-arrayexpress

Dextran sodium sulfate treatment of wild type and Pirc rats alters colonic normal tissue gene expression

Project description:Dextran sodium sulfate (DSS) causes inflammation in the gut similar to ulcerative colitis in humans. Patients with ulcerative colitis have increased risk of developing colon cancer. We sought to determine which genes are altered in the normal colonic epithelium, and which changes depend on the Pirc mutation. 97 day old (ACIxF344)F1 wild type and Pirc male rats either untreated or given 4% DSS in the drinking water from 40-47 and 54-61 days of age, housed in 12 hour light:12 dark, ad lib feeding. Normal colonic tissue was collected from the distal colon at 97 days of age.

2014-01-14 | E-GEOD-54005 | biostudies-arrayexpress

Suppression of plasmacytoid dendritic cell migration by compounds derived from natural medicines

Project description:Background and Aims. Dendritic cells (DCs) play a pivotal role in maintaining immunological homeostasis by orchestrating innate and adaptive immune responses via migration to inflamed sites and the lymph nodes (LNs). Plasmacytoid DCs (pDCs) have been reported to accumulate in the colon of inflammatory bowel disease (IBD) patients and dextran sulfate sodium (DSS)-induced colitis mice. However, the role of pDCs in the progression of colonic inflammation remains unclear. Methods. 80 compounds in natural medicines were searched for inhibitors of pDC migration using bone marrow-derived pDCs (BMpDCs) and conventional DCs (BMcDCs). BALB/c mice were given 3% DSS in the drinking water for 7 days to induce acute colitis. Compounds, which specifically inhibited pDC migration, were administrated into DSS-induced colitis mice. Results. Astragaloside IV (As-IV) and oxymatrine (Oxy) suppressed BMpDC migration but not BMcDC migration. In DSS-induced colitis mice, the number of pDCs was markedly increased in the colonic lamina propria (LP), and the expression of CCL21 was obviously observed in colonic isolated lymphoid follicles (ILFs). As-IV and Oxy reduced symptoms of colitis and the accumulation of pDCs in colonic ILFs but not in the colonic LP. Moreover, in a BMpDC adoptive transfer model, BMpDC migration to colonic ILFs was significantly decreased by treatment with As-IV or Oxy. Conclusion. pDCs accumulated in the colon of DSS-induced colitis mice, and As-IV and Oxy ameliorated DSS-induced colitis by suppressing pDC migration to colonic ILFs. Accordingly, the selective inhibition of pDC migration may be a potential therapeutic approach for treating colonic inflammatory diseases.

2021-07-06 | GSE167388 | GEO

Transcriptional analysis of resting or inflamed murine Macrophages with Immune complex stimulation

Project description:We wished to investigate differential effects of stimulation with immune complex on colonic macrophages taken from mice which were either healthy or had DSS induced colitis.

2019-03-18 | GSE109040 | GEO

The Tight Junction Protein Claudin-2 Controls Mucosal Permeability, Immune Tolerance and Colitis in Mice

Project description:The mucosal epithelium plays a key role in regulating immune homeostasis. Dysregulation of epithelial barrier function is associated with mucosal inflammation. Expression of claudin-2, a pore-forming tight junction protein, is highly upregulated during inflammatory bowel disease (IBD) and, due to its association with epithelial permeability, has been postulated to promote inflammation. Furthermore, claudin-2 also regulates colonic epithelial cell proliferation and intestinal nutrient absorption. However, the precise role of claudin-2 in regulating colonic epithelial and immune homeostasis remains unclear. Here, we demonstrate, using Villin-Claudin-2 transgenic (Cl-2TG) mice, that increased colonic claudin-2 expression unexpectedly protects mice against experimentally induced colitis and colitis-associated cancer. Notably, Cl-2TG mice exhibited increased colon length and permeability as compared with wild type (WT) littermates. However, despite their leaky colon, Cl-2TG mice subjected to experimental colitis were immune compromised, with reduced induction of TLR-2, TLR-4, Myd-88 expression and NF-kB and STAT3 activation. Most importantly, colonic macrophages in Cl-2TG mice exhibited an anergic phenotype. Claudin-2 overexpression also increased colonocyte proliferation and provided protection against colitis-induced colonocyte death. Taken together, our findings have revealed a critical role of claudin-2 in regulating colonic homeostasis, suggesting novel therapeutic strategies for inflammatory conditions of the gastrointestinal tract. 8-10 weeks old male Villin-Claudin-2 transgenic mice and WT littermates were provided either normal drinking water (control) or Dextran Sodium Sulfate (DSS: 4% w/v) for 10 days. 3 replicates each.

2013-09-15 | E-GEOD-46006 | biostudies-arrayexpress

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

Dextran sodium sulfate treatment of Pirc rats alters colonic and tumor gene expression

2014-01-14 | GSE54035 | GEO

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