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CCL25/CCR9 interactions regulate large intestinal inflammation in a murine model of acute colitis.

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 TNF?, IFN?, 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.

SUBMITTER: Wurbel MA

PROVIDER: S-EPMC3026821 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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CCL25/CCR9 interactions regulate large intestinal inflammation in a murine model of acute colitis.

Wurbel Marc-Andre MA McIntire Maria G MG Dwyer Peter P Fiebiger Edda E

PloS one 20110125 1

<h4>Background aims</h4>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.<h4>Methods</h4>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 den ...[more]

PMID: 21283540

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Project description:BackgroundOvarian carcinoma (OvCa) is the most lethal gynecological malignancy among women and its poor prognosis is mainly due to metastasis. Chemokine receptor CCR9 is primarily expressed by a small subset of immune cells and its only natural ligand, CCL25, is largely expressed in the thymus, which involutes with age. Other than the thymus, CCL25 is expressed by the small bowel. Interactions between CCL25 and CCR9 have been implicated in leukocyte trafficking to the small bowel, a frequent metastatic site for OvCa cells. The current study shows OvCa tissue and cells significantly express CCR9, which interacts with CCL25 to support carcinoma cell migration and invasion.MethodsRT-PCR and flow cytometry techniques were used to quantify the expression CCR9 by OvCa cells. OvCa tissue microarrays (TMA) was used to confirm CCR9 expression in clinical samples. The Aperio ScanScope scanning system was used to quantify immunohistochemical staining. Cell invasion and migration assays were performed using cell migration and matrigel invasion chambers. Matrix metalloproteinase (MMP) mRNAs were quantified by RT-PCR and active MMPs were quantified by ELISA.ResultsOur results show significantly (p<0.001) higher expression of CCR9 by mucinous adenocarcinoma, papillary serous carcinoma, and endometriod ovarian carcinoma cases, than compared to non-neoplastic ovarian tissue. Furthermore, CCR9 expression was significantly elevated in OvCa cell lines (OVCAR-3 and CAOV-3) in comparison to normal adult ovarian epithelial cell mRNA. OvCa cells showed higher migratory and invasive potential towards chemotactic gradients of CCL25, which was inhibited by anti-CCR9 antibodies. Expression of collagenases (MMP-1, -8, and -13), gelatinases (MMP-2 and -9), and stromelysins (MMP-3, -10, and -11) by OvCa cells were modulated by CCL25 in a CCR9-dependent fashion.ConclusionsThese results demonstrate both biological significance and clinical relevance of CCL25 and CCR9 interactions in OvCa cell metastasis.

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CCL25/CCR9 interactions regulate large intestinal inflammation in a murine model of acute colitis.

Publications

CCL25/CCR9 interactions regulate large intestinal inflammation in a murine model of acute colitis.

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