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

ABSTRACT 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.

Download full-text


Available from: Edda Fiebiger, Sep 27, 2015
20 Reads
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "CCR9 is thought to participate in the specific localization of T cells to the small intestines because the sole ligand for CCR9, C-C chemokine ligand 25 (CCL25), is strongly expressed by the small intestinal epithelium [33]. However, Wurbel et al. [34] revealed that CCL25 expression increased during the recovery phase after acute DSS administration, suggesting a regulatory role of CCR9/CCL25 interactions during colonic inflammation. In this study, percentages of PSGL-1-, LFA-1-, and CCR9-expressing T cells were upregulated in acute DSS colitis, whereas expression levels of α4β7 integrins in colitic mice did not differ from those of normal mice. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Migration of T cells into the colon plays a major role in the pathogenesis in inflammatory bowel disease. This study investigated the effects of glutamine (Gln) supplementation on chemokine receptors and adhesion molecules expressed by T cells in mice with dextran sulfate sodium- (DSS-) induced colitis. Methods: C57BL/6 mice were fed either a standard diet or a Gln diet replacing 25% of the total nitrogen. After being fed the diets for 5 days, half of the mice from both groups were given 1.5% DSS in drinking water to induce colitis. Mice were killed after 5 days of DSS exposure. Results: DSS colitis resulted in higher expression levels of P-selectin glycoprotein ligand- (PSGL-) 1, leukocyte function-associated antigen- (LFA-) 1, and C-C chemokine receptor type 9 (CCR9) by T helper (Th) and cytotoxic T (Tc) cells, and mRNA levels of endothelial adhesion molecules in colons were upregulated. Gln supplementation decreased expressions of PSGL-1, LFA-1, and CCR9 by Th cells. Colonic gene expressions of endothelial adhesion molecules were also lower in Gln-colitis mice. Histological finding showed that colon infiltrating Th cells were less in the DSS group with Gln administration. Conclusions: Gln supplementation may ameliorate the inflammation of colitis possibly via suppression of T cell migration.
    Mediators of Inflammation 05/2014; 2014:837107. DOI:10.1155/2014/837107 · 3.24 Impact Factor
  • Source
    • "Furthermore, it also supports the Monte Carlo effect, a hypothesis drawn about the biological importance that the level of mRNA expression is not always directly correlated with the protein expression [74]. In addition, the chemotactic ability of CCL25 not only is the result of a cellular receptor of CCR9, but also is receiving signals from other receptors and signaling cascades for activation, stimulation, and cellular migration [64]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Guided migration of chondrogenically differentiated cells has not been well studied before, even though it may be critical for growth, repair and regenerative processes. The chemokine CCL25 is believed to play a critical role in the directional migration of leukocytes and stem cells. To investigate the motility affect of serum or CCL25 mediated chemotaxis on chondrogenically differentiated cells, mesenchymal stem cells (MSC) were induced to chondrogenic lineage cells. MSC-derived chondrogenically differentiated cells were characterized for morphology, histology, immunohistochemistry, qPCR, surface profile and serum or CCL25 mediated cell migration. Additionally, the chemokine receptor, CCR9, was examined in different states of MSC. The chondrogenic differentiated state of MSC was positive for collagen type II and alcian blue staining, and showed significantly upregulated expression of COL2A1and SOX9, and downregulated expression of CD44, CD73, CD90, CD105 and CD166, in contrast to undifferentiated and dedifferentiated state of MSC. For chondrogenic differentiated, undifferentiated and dedifferentiated state of MSC, the serum mediated chemotaxis was in % ratio of 33:84:85, and CCL25 mediated chemotaxis was in % ratio of 12:14:13 respectively. On protein level, CCR9, receptor of CCL25, was expressed in the form of extracellular and intracellular domains. On gene level, qPCR confirmed the expression of CCR9 in different states of MSC. CCL25 is an effective cue to guide migration in a directional way. In CCL25 mediated chemotaxis, the cell migration rate was almost the same for different states of MSC. In serum mediated chemotaxis, the cell migration rate of chondrogenically differentiated cells was significantly lower than undifferentiated or dedifferentiated cells. Current knowledge of surface CD profile and cell migration could be beneficial for regenerative cellular therapies.
    Stem Cell Research & Therapy 08/2013; 4(4):99. DOI:10.1186/scrt310 · 3.37 Impact Factor
Show more