Dataset Information

Dynamics of Colon Monocyte and Macrophage Activation During Colitis.

ABSTRACT: Background: Macrophages are pivotal in coordinating a range of important processes in the intestines, including controlling intracellular infections and limiting damaging inflammation against the microbiota. However, it is not clear how gut macrophages, relative to recruited blood monocytes and other myeloid cells, contribute to the intestinal inflammatory milieu, nor how macrophages and their monocyte precursors mediate recruitment of other immune cells to the inflamed intestine. Methods: Myeloid cell populations isolated from colonic inflammatory bowel disease (IBD) or murine dextran sulphate sodium (DSS) induced colitis were assessed using flow cytometry and compared to healthy controls. In addition, mRNA expression profiles in human and murine colon samples, and in macrophages and monocytes from healthy and inflamed murine colons, were analysed by quantitative PCR (qPCR) and mRNA microarray. Results: We show that the monocyte:macrophage balance is disrupted in colon inflammation to favour recruitment of CD14+HLA-DRInt cells in humans, and Ly6CHi monocytes in mice. In addition, we identify that murine blood monocytes receive systemic signals enabling increased release of IL-1? prior to egress from the blood into the colon. Further, once within the colon and relative to other myeloid cells, monocytes represent the dominant local source of both IL-1? and TNF. Finally, our data reveal that, independent of inflammation, murine colon macrophages act as a major source of Ccl7 and Ccl8 chemokines that trigger further recruitment of their pro-inflammatory monocyte precursors. Conclusions: Our work suggests that strategies targeting macrophage-mediated monocyte recruitment may represent a promising approach for limiting the chronic inflammation that characterises IBD.

SUBMITTER: Jones GR

PROVIDER: S-EPMC6277765 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Dynamics of Colon Monocyte and Macrophage Activation During Colitis.

Jones Gareth-Rhys GR Bain Calum C CC Fenton Thomas M TM Kelly Aoife A Brown Sheila L SL Ivens Alasdair C AC Travis Mark A MA Cook Peter C PC MacDonald Andrew S AS

Frontiers in immunology 20181127

<b>Background:</b> Macrophages are pivotal in coordinating a range of important processes in the intestines, including controlling intracellular infections and limiting damaging inflammation against the microbiota. However, it is not clear how gut macrophages, relative to recruited blood monocytes and other myeloid cells, contribute to the intestinal inflammatory milieu, nor how macrophages and their monocyte precursors mediate recruitment of other immune cells to the inflamed intestine. <b>Meth ...[more]

PMID: 30542349

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Project description:To investigate efficacy and safety for granulocyte, monocyte apheresis in a population of pediatric patients with ulcerative colitis.The ADAPT study was a prospective, open-label, multicenter study in pediatric patients with moderate, active ulcerative colitis with pediatric ulcerative colitis activity index (PUCAI) of 35-64. Patients received one weekly apheresis with Adacolumn(®) granulocyte, monocyte/macrophage adsorptive (GMA) apheresis over 5 consecutive weeks, optionally followed by up to 3 additional apheresis treatments over 3 consecutive weeks. The primary endpoint was the change in mean PUCAI between baseline and week 12; the secondary endpoint was improvement in PUCAI categorized as (Significant Improvement, PUCAI decrease of ? 35), Moderate Improvement (PUCAI decrease of 20 < 35), Small Improvement (PUCAI decrease of 10 < 20) or No change (PUCAI decrease of < 10).Twenty-five patients (mean age 13.5 years; mean weight 47.7 kg) were enrolled. In the intention-to-treat set (ITT), the mean value for PUCAI improvement was 22.3 [95%CI: 12.9-31.6; n = 21]. In the per-protocol (PP) set, the mean improvement was 36.3 [95%CI: 31.4-41.1; n = 8]. Significant Improvement was recorded for 9 out of 20 patients (45%); 5 out of 20 patients (25%) had Moderate Improvement and one patient (5%) had No Change in PUCAI score at week 12. In the PP set, six out of eight patients (75%) showed Significant Improvement; and in two out of eight patients (25%) Moderate Improvement was recorded. The endoscopic activity index (EAI) decreased by 3 points on average. Seven (7) out of 21 (33%) patients in ITT and 4 out of 8 (50%) patients in PP have used steroids during the clinical investigation. The mean steroid dosage for these patients in the ITT set decreased from a mean 12.4 mg to 10 mg daily on average from Baseline to week 12.Adacolumn(®) GMA apheresis treatment was effective in pediatric patients with moderate active Ulcerative Colitis. No new safety signals were reported. The present data contribute to considering GMA apheresis as a therapeutic option in pediatric patients having failed first line therapy.

Project description:Epidermal growth factor receptor (EGFR) signaling is a known mediator of colorectal carcinogenesis. Studies have focused on the role of EGFR signaling in epithelial cells, although the exact nature of the role of EGFR in colorectal carcinogenesis remains a topic of debate. Here, we present evidence that EGFR signaling in myeloid cells, specifically macrophages, is critical for colon tumorigenesis in the azoxymethane-dextran sodium sulfate (AOM-DSS) model of colitis-associated carcinogenesis (CAC). In a human tissue microarray, colonic macrophages demonstrated robust EGFR activation in the pre-cancerous stages of colitis and dysplasia. Utilizing the AOM-DSS model, mice with a myeloid-specific deletion of Egfr had significantly decreased tumor multiplicity and burden, protection from high-grade dysplasia and significantly reduced colitis. Intriguingly, mice with gastrointestinal epithelial cell-specific Egfr deletion demonstrated no differences in tumorigenesis in the AOM-DSS model. The alterations in tumorigenesis in myeloid-specific Egfr knockout mice were accompanied by decreased macrophage, neutrophil and T-cell infiltration. Pro-tumorigenic M2 macrophage activation was diminished in myeloid-specific Egfr-deficient mice, as marked by decreased Arg1 and Il10 mRNA expression and decreased interleukin (IL)-4, IL10 and IL-13 protein levels. Surprisingly, diminished M1 macrophage activation was also detectable, as marked by significantly reduced Nos2 and Il1b mRNA levels and decreased interferon (IFN)-?, tumor necrosis factor (TNF)-? and IL-1? protein levels. The alterations in M1 and M2 macrophage activation were confirmed in bone marrow-derived macrophages from mice with the myeloid-specific Egfr knockout. The combined effect of restrained M1 and M2 macrophage activation resulted in decreased production of pro-angiogenic factors, CXCL1 and vascular endothelial growth factor (VEGF), and reduced CD31+ blood vessels, which likely contributed to protection from tumorigenesis. These data reveal that EGFR signaling in macrophages, but not in colonic epithelial cells, has a significant role in CAC. EGFR signaling in macrophages may prove to be an effective biomarker of CAC or target for chemoprevention in patients with inflammatory bowel disease.

Dataset Information

Dynamics of Colon Monocyte and Macrophage Activation During Colitis.

Publications

Dynamics of Colon Monocyte and Macrophage Activation During Colitis.

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