CCL25/CCR9 Interactions Regulate Large Intestinal Inflammation in a Murine Model of Acute Colitis

Division of Gastroenterology and Nutrition, Children's Hospital Boston, and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS ONE (Impact Factor: 3.23). 01/2011; 6(1):e16442. DOI: 10.1371/journal.pone.0016442
Source: PubMed


CCL25/CCR9 is a non-promiscuous chemokine/receptor pair and a key regulator of leukocyte migration to the small intestine. We investigated here whether CCL25/CCR9 interactions also play a role in the regulation of inflammatory responses in the large intestine.
Acute inflammation and recovery in wild-type (WT) and CCR9(-/-) mice was studied in a model of dextran sulfate sodium (DSS)-induced colitis. Distribution studies and phenotypic characterization of dendritic cell subsets and macrophage were performed by flow cytometry. Inflammatory bowel disease (IBD) scores were assessed and expression of inflammatory cytokines was studied at the mRNA and the protein level.
CCL25 and CCR9 are both expressed in the large intestine and are upregulated during DSS colitis. CCR9(-/-) mice are more susceptible to DSS colitis than WT littermate controls as shown by higher mortality, increased IBD score and delayed recovery. During recovery, the CCR9(-/-) colonic mucosa is characterized by the accumulation of activated macrophages and elevated levels of Th1/Th17 inflammatory cytokines. Activated plasmacytoid dendritic cells (DCs) accumulate in mesenteric lymph nodes (MLNs) of CCR9(-/-) animals, altering the local ratio of DC subsets. Upon re-stimulation, T cells isolated from these MLNs secrete significantly higher levels of TNFα, IFNγ, IL2, IL-6 and IL-17A while down modulating IL-10 production.
Our results demonstrate that CCL25/CCR9 interactions regulate inflammatory immune responses in the large intestinal mucosa by balancing different subsets of dendritic cells. These findings have important implications for the use of CCR9-inhibitors in therapy of human IBD as they indicate a potential risk for patients with large intestinal inflammation.

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    • "Similarly, CXCL10 has been shown to be upregulated during UC [18], while CD tissues have been shown to express CXCR3, CXCL10, and CXCL9 [19] [20]. Chemokine CCL25, also known as thymus-expressed chemokine (TECK), a key regulator of leukocyte migration in the small intestine, is known to regulate intestinal inflammation [21]. Monocyte chemoattractant protein 1 (MCP-1) that attracts monocytes among other cells plays a critical role in colitis and is increased in IBD patients [22] [23]. "
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    ABSTRACT: Crohn's disease (CD) and ulcerative colitis (UC), two forms of inflammatory bowel disease (IBD), are chronic, relapsing, and tissue destructive lesions that are accompanied by the uncontrolled activation of effector immune cells in the mucosa. Recent estimates indicate that there are 1.3 million annual cases of IBD in the United States, 50% of which consists of CD and 50% of UC. Chemokines and cytokines play a pivotal role in the regulation of mucosal inflammation by promoting leukocyte migration to sites of inflammation ultimately leading to tissue damage and destruction. In recent years, experimental studies in rodents have led to a better understanding of the role played by these inflammatory mediators in the development and progression of colitis. However, the clinical literature on IBD remains limited. Therefore, the aim of this study was to evaluate systemic concentrations of key chemokines and cytokines in forty-two IBD patients with a range of disease activity compared to levels found in ten healthy donors. We found a significant increase in an array of chemokines including macrophage migration factor (MIF), CCL25, CCL23, CXCL5, CXCL13, CXCL10, CXCL11, MCP1, and CCL21 in IBD patients as compared to normal healthy donors (P<0.05). Further, we also report increases in the inflammatory cytokines IL-16, IFN-γ, IL-1β and TNF-α in IBD patients when compared to healthy donors (P<0.05). These data clearly indicate an increase in circulating levels of specific chemokines and cytokines that are known to modulate systemic level through immune cells results in affecting local intestinal inflammation and tissue damage in IBD patients. Blockade of these inflammatory mediators should be explored as a mechanism to alleviate or even reverse symptoms of IBD.
    Cytokine 11/2015; 77:44-49. DOI:10.1016/j.cyto.2015.10.008 · 2.66 Impact Factor
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    • "In colon from inflammatory bowel disease (IBD) patients with active colonic inflammation, CCL25 mRNA was detected by one group [17] but not by two others [16] [18]. CCL25 mRNA was recently detected in mouse colon and was found to be upregulated in the DSS model of acute colitis [19]. An early report indicated that the increased frequency of circulating CCR9 + T cells observed in Crohn's disease patients was not observed "
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    ABSTRACT: While it has long been established that the chemokine receptor CCR9 and its ligand CCL25 are essential for the movement of leukocytes into the small intestine and the development of small-intestinal inflammation, the role of this chemokine-receptor pair in colonic inflammation is not clear. Toward this end, we compared colonic CCL25 protein levels in healthy individuals to those in patients with ulcerative colitis. In addition, we determined the effect of CCR9 pharmacological inhibition in the mdr1a −/− mouse model of ulcerative colitis. Colon samples from patients with ulcerative colitis had significantly higher levels of CCL25 protein compared to healthy controls, a finding mirrored in the mdr1a −/− mice. In the mdr1a −/− mice, CCR9 antagonists significantly decreased the extent of wasting and colonic remodeling and reduced the levels of inflammatory cytokines in the colon. These findings indicate that the CCR9:CCL25 pair plays a causative role in ulcerative colitis and suggest that CCR9 antagonists will provide a therapeutic benefit in patients with colonic inflammation.
    Mediators of Inflammation 10/2015; 2015(5):628340. DOI:10.1155/2015/628340 · 3.24 Impact Factor
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    • "A low-level of expression for CCL25 and CCR9 has been detected in the large intestine [30]. To determine whether colitis affects the expression levels of NK1.1, CCL25 and CCR9, we analyzed the mRNA expression levels using qPCR. "
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    ABSTRACT: Background Natural killer T (NKT) cells share phenotypic and functional properties with both conventional natural killer cells and T cells. These cells might have an important role in the pathogenesis of ulcerative colitis (UC). The interaction of chemokine ligand 25 (CCL25) with chemokine receptor 9 (CCR9) is involved in gut-specific migration of leukocytes and induces regulatory T cells (Tregs) to migrate to the intestine in chronic ileitis. Methodology/Findings In UC patients, NKT receptor CD161, CCL25, and CCR9 expression levels were evaluated by qRT-PCR. A murine model of oxazolone-induced colitis was induced in BALB/c mice. The mRNA levels of NK1.1, CCL25 and CCR9, and pro-inflammatory cytokines in mice were evaluated. The CCR9 expression on Type I or invariant NKT (iNKT) cells, and the iNKT cells chemotaxis are observed according to flow cytometry. NKT receptor CD161, CCL25 and CCR9 expression levels were significantly increased in UC patients. And, the mRNA expression levels of NK1.1, CCL25 and CCR9 were increased in oxazolone-induced colitis in mice. The production of pro-inflammatory cytokines was significantly increased, especially interleukin 4 (IL-4), IL-10 and IL-13. We observed significantly increased CCR9 expression on iNKT cells. Furthermore, we found an increased iNKT population and enhanced chemotaxis during oxazolone-induced colitis. Conclusions/Significance Our study suggests that CCL25/CCR9 interactions may promote the induction and function of iNKT cells during oxazolone-induced colitis. These findings may have important implications for UC treatment and suggest a role for CCR9 inhibitors.
    PLoS ONE 06/2014; 9(6):e100167. DOI:10.1371/journal.pone.0100167 · 3.23 Impact Factor
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