title: CCL25/CCR9 interactions regulate large intestinal inflammation in a murine model of acute colitis.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Gastroenterology and Nutrition, Children's Hospital Boston, and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, United States of America. marc-andre.wurbel@childrens.harvard.edu
authors.forename: Marc-Andre
authors.initials: MA
authors.lastname: Wurbel
authors.forename: Maria G
authors.initials: MG
authors.lastname: McIntire
authors.forename: Peter
authors.initials: P
authors.lastname: Dwyer
authors.forename: Edda
authors.initials: E
authors.lastname: Fiebiger
mesh_terms: D000208:Acute Disease; D000818:Animals; D019742:Chemokines, CC / Q000276:immunology* / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000276:immunology*; D016207:Cytokines; D003713:Dendritic Cells / Q000276:immunology*; D016264:Dextran Sulfate; D007413:Intestinal Mucosa / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding / Q000276:immunology; D054388:Receptors, CCR / Q000276:immunology* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology
chemical_list: C119309:CC chemokine receptor 9; C491541:Ccl25 protein, mouse; D019742:Chemokines, CC; D016207:Cytokines; D054388:Receptors, CCR; D016264:Dextran Sulfate