title: Role of beta7 integrin and the chemokine/chemokine receptor pair CCL25/CCR9 in modeled TNF-dependent Crohn's disease.
abstract: OBJECTIVE
  In the present work, we address the requirement for intestinal-specific homing molecules, the chemokine/chemokine receptor pair CCL25/CCR9 and beta7 integrin, in the pathogenesis of the CD8(+) T cell-dependent Tnf(DeltaARE) mouse model of Crohn's-like inflammatory bowel disease.
  
  
  METHODS
  We investigated by flow cytometry lymphocyte recruitment in the intestinal epithelium and lamina propria (LP); cytokine production by intraepithelial and LP lymphocytes; and peripheral expression of CCR9, alpha4beta7, and alphaEbeta7 integrin. The functional significance of CCL25/CCR9 and beta7 integrin in inflammatory lymphocyte recruitment and intestinal disease development was assessed in Tnf(DeltaARE) mice genetically lacking these molecules.
  
  
  RESULTS
  Intestinal inflammation in the Tnf(DeltaARE) mice is associated with early reduction of CD8alphaalpha-expressing intraepithelial lymphocytes, decreased T helper cell 1 and increased T helper cell 17 responses by LP CD4(+) lymphocytes, increased alphaEbeta7 integrin expression in peripheral activated/memory intestinal-homing CD8alphabeta lymphocytes, and predominance of tumor necrosis factor/interferon-gamma-producing CD8alphabeta lymphocytes in the epithelium. Although CCL25/CCR9 have been strongly implicated in T-lymphocyte recruitment to the small intestine, inflammatory pathology develops unperturbed in the genetic absence of CCL25/CCR9. Furthermore, CD8alphabeta lymphocyte recruitment in the intestinal epithelium and inflammatory infiltration in the LP are not impaired in CCR9- or CCL25-deficient Tnf(DeltaARE) mice. In contrast, genetic ablation of beta7 integrin results in complete amelioration of intestinal pathology.
  
  
  CONCLUSIONS
  Our findings demonstrate that development of intestinal inflammation in the Tnf(DeltaARE) mice is critically dependent on beta7 integrin-mediated T-lymphocyte recruitment, whereas the function of the CCL25/CCR9 axis appears dispensable in this model.
authors.affiliation: Institute of Immunology, Biomedical Sciences Research Center Alexander Fleming, Vari, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Apostolaki
authors.forename: Menelaos
authors.initials: M
authors.lastname: Manoloukos
authors.forename: Manolis
authors.initials: M
authors.lastname: Roulis
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Wurbel
authors.forename: Werner
authors.initials: W
authors.lastname: Müller
authors.forename: Konstantinos A
authors.initials: KA
authors.lastname: Papadakis
authors.forename: Dimitris L
authors.initials: DL
authors.lastname: Kontoyiannis
authors.forename: Bernard
authors.initials: B
authors.lastname: Malissen
authors.forename: George
authors.initials: G
authors.lastname: Kollias
mesh_terms: D000818:Animals; D016827:CD8 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D003106:Colon / Q000276:immunology* / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D039641:Integrin beta Chains / Q000235:genetics / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054388:Receptors, CCR / Q000235:genetics / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: C119309:CC chemokine receptor 9; D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; C433839:CD8alphabeta antigen; C491541:Ccl25 protein, mouse; D019742:Chemokines, CC; D039641:Integrin beta Chains; D016023:Integrins; D054388:Receptors, CCR; D014409:Tumor Necrosis Factor-alpha; C071777:integrin alpha4beta7; C070709:integrin alphaEbeta7; C091368:integrin beta7; D007371:Interferon-gamma