Colonic Eosinophilic Inflammation in Experimental Colitis Is Mediated by Ly6Chigh CCR2+ Inflammatory Monocyte/Macrophage-Derived CCL11

Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
The Journal of Immunology (Impact Factor: 4.92). 05/2011; 186(10):5993-6003. DOI: 10.4049/jimmunol.1003844
Source: PubMed


Recent genome-wide association studies of pediatric inflammatory bowel disease have implicated the 17q12 loci, which contains the eosinophil-specific chemokine gene CCL11, with early-onset inflammatory bowel disease susceptibility. In the current study, we employed a murine model of experimental colitis to define the molecular pathways that regulate CCL11 expression in the chronic intestinal inflammation and pathophysiology of experimental colitis. Bone marrow chimera experiments showed that hematopoietic cell-derived CCL11 is sufficient for CCL11-mediated colonic eosinophilic inflammation. We show that dextran sodium sulfate (DSS) treatment promotes the recruitment of F4/80(+)CD11b(+)CCR2(+)Ly6C(high) inflammatory monocytes into the colon. F4/80(+)CD11b(+)CCR2(+)Ly6C(high) monocytes express CCL11, and their recruitment positively correlated with colonic eosinophilic inflammation. Phenotypic analysis of purified Ly6C(high) intestinal inflammatory macrophages revealed that these cells express both M1- and M2-associated genes, including Il6, Ccl4, Cxcl2, Arg1, Chi3l3, Ccl11, and Il10, respectively. Attenuation of DSS-induced F4/80(+)CD11b(+)CCR2(+)Ly6C(high) monocyte recruitment to the colon in CCR2(-/-) mice was associated with decreased colonic CCL11 expression, eosinophilic inflammation, and DSS-induced histopathology. These studies identify a mechanism for DSS-induced colonic eosinophilia mediated by Ly6C(high)CCR2(+) inflammatory monocyte/macrophage-derived CCL11.

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Available from: Ariel Munitz
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    • "More recently, eotaxin-1 has been shown to be increased in the sputum and intestinal biopsies of pediatric patients with asthma and eosinophilic gastrointestinal diseases [29]. Additionally, tissue eotaxin-1 mRNA levels have been shown to be increased in a study of 13 pediatric UC cases [30] compared to controls, which was similar to our findings that eotaxin-1 mRNA expression was increased in 46 adult UC cases studied that were compared to 22 controls. "
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    ABSTRACT: Accurate and high-throughput technologies are needed for identification of new therapeutic targets and for optimizing therapy in inflammatory bowel disease. Our aim was to assess multi-analyte protein-based assays of cytokines/chemokines using Luminex technology. We have reported that Luminex-based profiling was useful in assessing response to L-arginine therapy in the mouse model of dextran sulfate sodium colitis. Therefore, we studied prospectively collected samples from ulcerative colitis (UC) patients and control subjects. Serum, colon biopsies, and clinical information were obtained from subjects undergoing colonoscopy for evaluation of UC or for non-UC indications. In total, 38 normal controls and 137 UC cases completed the study. Histologic disease severity and the Mayo Disease Activity Index (DAI) were assessed. Serum and colonic tissue cytokine/chemokine profiles were measured by Luminex-based multiplex testing of 42 analytes. Only eotaxin-1 and G-CSF were increased in serum of patients with histologically active UC vs. controls. While 13 cytokines/chemokines were increased in active UC vs. controls in tissues, only eotaxin-1 was increased in all levels of active disease in both serum and tissue. In tissues, eotaxin-1 correlated with the DAI and with eosinophil counts. Increased eotaxin-1 levels were confirmed by real-time PCR. Tissue eotaxin-1 levels were also increased in experimental murine colitis induced by dextran sulfate sodium, oxazolone, or Citrobacter rodentium, but not in murine Helicobacter pylori infection. Our data implicate eotaxin-1 as an etiologic factor and therapeutic target in UC, and indicate that Luminex-based assays may be useful to assess IBD pathogenesis and to select patients for anti-cytokine/chemokine therapies.
    Full-text · Article · Dec 2013 · PLoS ONE
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    • "Ly6Chi monocytes are characterized by high expression of the chemokine receptor CCR2, adhesion molecule CD62L and low expression of the fractalkine receptor CX3CR1[48,51,58]. These cells have been termed ‘inflammatory’ because they are selectively recruited to sites of inflammation and infection in many models of disease, including atherosclerosis [59-62]; rheumatoid arthritis [63]; experimental colitis [64]; cardiac infarction [65]; and CNS infections including experimental autoimmune encephalomyelitis (EAE) [66,67], amyotrophic lateral sclerosis [68], and stroke [53]. Recent studies have shown that these cells are also recruited to the virus-infected brain in animal models of HSV, HIV, murine hepatitis virus (MHV), Theiler’s murine encephalomyelitis virus (TMEV) and a number of flaviviral encephalitides, where they give rise to macrophage, DC and, arguably, to microglial populations [11,13,14,69]. "
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    ABSTRACT: Monocytes are a heterogeneous population of bone marrow-derived cells that are recruited to sites of infection and inflammation in many models of human diseases, including those of the central nervous system (CNS). Ly6Chi/CCR2hi inflammatory monocytes have been identified as the circulating precursors of brain macrophages, dendritic cells and arguably microglia in experimental autoimmune encephalomyelitis; Alzheimer's disease; stroke; and more recently in CNS infection caused by Herpes simplex virus, murine hepatitis virus, Theiler's murine encephalomyelitis virus, Japanese encephalitis virus and West Nile virus. The precise differentiation pathways and functions of inflammatory monocyte-derived populations in the inflamed CNS remains a contentious issue, especially in regard to the existence of monocyte-derived microglia. Furthermore, the contributions of monocyte-derived subsets to viral clearance and immunopathology are not well-defined. Thus, understanding the pathways through which inflammatory monocytes migrate to the brain and their functional capacity within the CNS is critical to inform future therapeutic strategies. This review discusses some of the key aspects of inflammatory monocyte trafficking to the brain and addresses the role of these cells in viral encephalitis.
    Full-text · Article · Dec 2012 · Journal of Neuroinflammation
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    • "Monocyte Descendants in the Inflamed Colon accordance with earlier reports on other colitis models (Rivollier et al., 2012; Weber et al., 2011) or DSS-induced colitis (Platt et al., 2010; Waddell et al., 2011), flow cytometry analysis of the inflamed colonic lamina propria revealed the progressive emergence of CX 3 CR1-GFP int cells concomitant with a marked reduction in the frequency of CX 3 CR1-GFP hi resident macrophages (Figure 2A). The accumulation of CX 3 CR1-GFP int cells reached its peak at day 7 after the initial DSS exposure, outnumbering CX 3 CR1-GFP hi resident macrophages by 10-fold, and was associated with neutrophil infiltration and significant destruction of the crypt architecture, as determined by histology (Figures 2A– 2C). "
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    ABSTRACT: Ly6C(hi) monocytes seed the healthy intestinal lamina propria to give rise to resident CX(3)CR1(+) macrophages that contribute to the maintenance of gut homeostasis. Here we report on two alternative monocyte fates in the inflamed colon. We showed that CCR2 expression is essential to the recruitment of Ly6C(hi) monocytes to the inflamed gut to become the dominant mononuclear cell type in the lamina propria during settings of acute colitis. In the inflammatory microenvironment, monocytes upregulated TLR2 and NOD2, rendering them responsive to bacterial products to become proinflammatory effector cells. Ablation of Ly6C(hi) monocytes ameliorated acute gut inflammation. With time, monocytes differentiated into migratory antigen-presenting cells capable of priming naive T cells, thus acquiring hallmarks reminiscent of dendritic cells. Collectively, our results highlight cellular dynamics in the inflamed colon and the plasticity of Ly6C(hi) monocytes, marking them as potential targets for inflammatory bowel disease (IBD) therapy.
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