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M2 macrophages activate WNT signaling pathway in epithelial cells: relevance in ulcerative colitis.

ABSTRACT: Macrophages, which exhibit great plasticity, are important components of the inflamed tissue and constitute an essential element of regenerative responses. Epithelial Wnt signalling is involved in mechanisms of proliferation and differentiation and expression of Wnt ligands by macrophages has been reported. We aim to determine whether the macrophage phenotype determines the expression of Wnt ligands, the influence of the macrophage phenotype in epithelial activation of Wnt signalling and the relevance of this pathway in ulcerative colitis. Human monocyte-derived macrophages and U937-derived macrophages were polarized towards M1 or M2 phenotypes and the expression of Wnt1 and Wnt3a was analyzed by qPCR. The effects of macrophages and the role of Wnt1 were analyzed on the expression of ?-catenin, Tcf-4, c-Myc and markers of cell differentiation in a co-culture system with Caco-2 cells. Immunohistochemical staining of CD68, CD206, CD86, Wnt1, ?-catenin and c-Myc were evaluated in the damaged and non-damaged mucosa of patients with UC. We also determined the mRNA expression of Lgr5 and c-Myc by qPCR and protein levels of ?-catenin by western blot. Results show that M2, and no M1, activated the Wnt signaling pathway in co-culture epithelial cells through Wnt1 which impaired enterocyte differentiation. A significant increase in the number of CD206+ macrophages was observed in the damaged mucosa of chronic vs newly diagnosed patients. CD206 immunostaining co-localized with Wnt1 in the mucosa and these cells were associated with activation of canonical Wnt signalling pathway in epithelial cells and diminution of alkaline phosphatase activity. Our results show that M2 macrophages, and not M1, activate Wnt signalling pathways and decrease enterocyte differentiation in co-cultured epithelial cells. In the mucosa of UC patients, M2 macrophages increase with chronicity and are associated with activation of epithelial Wnt signalling and diminution in enterocyte differentiation.

SUBMITTER: Cosin-Roger J

PROVIDER: S-EPMC3805515 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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M2 macrophages activate WNT signaling pathway in epithelial cells: relevance in ulcerative colitis.

Cosín-Roger Jesús J Ortiz-Masiá Dolores D Calatayud Sara S Hernández Carlos C Alvarez Angeles A Hinojosa Joaquin J Esplugues Juan V JV Barrachina Maria D MD

PloS one 20131022 10

Macrophages, which exhibit great plasticity, are important components of the inflamed tissue and constitute an essential element of regenerative responses. Epithelial Wnt signalling is involved in mechanisms of proliferation and differentiation and expression of Wnt ligands by macrophages has been reported. We aim to determine whether the macrophage phenotype determines the expression of Wnt ligands, the influence of the macrophage phenotype in epithelial activation of Wnt signalling and the rel ...[more]

PMID: 24167598

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Project description:AimsThe potential signaling pathways and core genes in ulcerative colitis (UC) were investigated in this study. Furthermore, potential mechanisms of BBR in treating UC were also explored.MethodsExpression profiling by array of UC patients were obtained from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were determined with the differential analysis. The biological functions of DEGs were analyzed through the Database for Annotation, Visualization and Integrated Discovery (DAVID). The Gene Set Enrichment Analysis (GSEA) was applied to analyze the expression differences between two different phenotype sample sets. Dextran sulfate sodium (DSS) was applied to establish UC model of mice and lipopolysaccharide (LPS) was utilized to induce inflammatory damage of NCM460 cells. Therapeutic effects of berberine (BBR) on disease performance, pathologic changes and serum supernatant indices were analyzed in vivo. To further investigate the potential mechanisms of BBR in treating UC, the expression of genes and proteins in vivo and in vitro were examined by RT-qPCR, immunohistochemical staining and western blotting.ResultsImmune-inflammatory genes were identified and up-regulated significantly in UC patients. In addition, IFN-γ signaling pathway and its core genes were significantly up-regulated in the phenotype of UC. All disease performance and the pathologic changes of UC in mice were evidently ameliorated by BBR treatment. The pro-inflammatory cytokines of serum, including CXCL9, CXCL1, IL-17 and TNF-α, in UC mice were significantly reduced by treatment of BBR. In terms of mechanisms of BBR in treating UC, the pro-inflammatory and immune-related genes, encoding IFN-γ, IRF8, NF-κB and TNF-α decreased significantly in UC mice followed by BBR treatment. Meanwhile, the expression of IFN-γ and its initiated targets, including IRF8, Ifit1, Ifit3, IRF1, were suppressed significantly by BBR treatment in vivo. The blocking of IFN-γ in vitro led to the silence of IFN-γ signaling pathway after exposure to BBR. Furthermore, the blocking of IFN-γ in vitro led to the silence of IFN-γ signaling pathway after exposure to BBR.ConclusionBBR holds anti-inflammatory activity and can treat UC effectively. The anti-inflammatory property of BBR is tightly related to the suppression of IFN-γ signaling pathway, which is crucial in immune-inflammatory responses of the colon mucosa.

Project description:BackgroundIncreasing evidence is suggesting appendectomy as an alternative treatment for ulcerative colitis (UC), especially in case of histological appendiceal inflammation. Therefore, preoperative identification of appendiceal inflammation could be beneficial. This study aimed to assess the prevalence of peri-appendiceal red patch (PARP) on colonoscopy. In addition, prognostic relevance of PARP for disease course and its predictive value for histological appendiceal inflammation in patients undergoing appendectomy was assessed.MethodsUC patients undergoing colonoscopy in 2014/2015 were included to determine PARP-prevalence in a cross-sectional study. Findings were correlated to patient and disease characteristics, upscaling of treatment and colectomy rates after cross-sectional colonoscopy. In patients undergoing appendiceal resection, histopathological inflammation was assessed using the Robarts Histopathology Index (RHI).ResultsIn total, 249 patients were included of which 17.7% (44/249) had a PARP. Patients with PARP were significantly younger with a shorter disease course. The majority of patients with PARP (61.4%) was in endoscopic remission. Patients with PARP required more upscaling of medical therapy (81.8% vs. 58.0%, p < 0.01), and more PARP patients underwent colectomy (13.6% vs. 4.9%, p = 0.04). Patients with PARP had a higher median RHI in resection specimens (14 vs. 7, p < 0.01).ConclusionPARP was present during colonoscopy regardless disease activity and was predominantly found in UC patients with younger age and shorter disease duration. PARP patients had a more severe course of UC, and in case of appendectomy, more severe histopathological appendiceal inflammation. Appendectomy as an experimental therapy for UC has been suggested to be predominantly effective in UC patients with appendiceal inflammation. This study demonstrates that presence of a PARP on colonoscopy predicts appendiceal inflammation. After consensus has been reached on the therapeutic effect of appendectomy, assessing PARP presence during colonoscopy could therefore contribute to identifying patients most likely to respond.

Project description:The acute myeloid leukemia (AML)-associated translocation products AML1-ETO, PML-retinoic acid receptor alpha (RARalpha), and PLZF-RARalpha encode aberrant transcription factors. Several lines of evidence suggest similar pathogenetic mechanisms for these fusion proteins. We used high-density oligonucleotide arrays to identify shared target genes in inducibly transfected U937 cells expressing AML1-ETO, PML-RARalpha, or PLZF-RARalpha. All three fusion proteins significantly repressed the expression of 38 genes and induced the expression of 14 genes. Several of the regulated genes were associated with Wnt signaling. One of these, plakoglobin (gamma-catenin), was induced on the mRNA and protein level by all three fusion proteins. In addition, primary AML blasts carrying one of the fusion proteins significantly overexpressed plakoglobin. The plakoglobin promoter was cloned and shown to be induced by AML1-ETO, with promoter activation depending on the corepressor and histone deacetylase binding domains. The induction of plakoglobin by AML fusion proteins led to downstream signaling and transactivation of TCF- and LEF-dependent promoters, including the c-myc promoter, which was found to be bound by plakoglobin in vivo after AML1-ETO expression. beta-Catenin protein levels and TCF and LEF target genes such as c-myc and cyclin D1 were found to be induced by the fusion proteins. On the functional level, a dominant negative TCF inhibited colony growth of AML1-ETO-positive Kasumi cells, whereas plakoglobin transfection into myeloid 32D cells enhanced proliferation and clonal growth. Injection of plakoglobin-expressing 32D cells into syngeneic mice accelerated the development of leukemia. Transduction of plakoglobin into primitive murine hematopoietic progenitor cells preserved the immature phenotype during colony growth, suggesting enhanced self-renewal. These data provide evidence that activation of Wnt signaling is a common feature of several balanced translocations in AML.

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M2 macrophages activate WNT signaling pathway in epithelial cells: relevance in ulcerative colitis.

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M2 macrophages activate WNT signaling pathway in epithelial cells: relevance in ulcerative colitis.

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