Role of β7 Integrin and the Chemokine/Chemokine Receptor Pair CCL25/CCR9 in Modeled TNF-Dependent Crohn's Disease

Maria Apostolaki, Menelaos Manoloukos, Manolis Roulis, Marc André Wurbel, Werner Müller, Konstantinos A. Papadakis, Dimitris L. Kontoyiannis, Bernard Malissen, George Kollias

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Abstract

Background & Aims: In the present work, we address the requirement for intestinal-specific homing molecules, the chemokine/chemokine receptor pair CCL25/CCR9 and β7 integrin, in the pathogenesis of the CD8+ T cell-dependent TnfΔARE 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, α4β7, and αEβ7 integrin. The functional significance of CCL25/CCR9 and β7 integrin in inflammatory lymphocyte recruitment and intestinal disease development was assessed in TnfΔARE mice genetically lacking these molecules. Results: Intestinal inflammation in the TnfΔARE mice is associated with early reduction of CD8αα-expressing intraepithelial lymphocytes, decreased T helper cell 1 and increased T helper cell 17 responses by LP CD4+ lymphocytes, increased αEβ7 integrin expression in peripheral activated/memory intestinal-homing CD8αβ lymphocytes, and predominance of tumor necrosis factor/interferon-γ-producing CD8αβ 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, CD8αβ lymphocyte recruitment in the intestinal epithelium and inflammatory infiltration in the LP are not impaired in CCR9- or CCL25-deficient TnfΔARE mice. In contrast, genetic ablation of β7 integrin results in complete amelioration of intestinal pathology. Conclusions: Our findings demonstrate that development of intestinal inflammation in the TnfΔARE mice is critically dependent on β7 integrin-mediated T-lymphocyte recruitment, whereas the function of the CCL25/CCR9 axis appears dispensable in this model.

Original languageEnglish (US)
Pages (from-to)2025-2035
Number of pages11
JournalGastroenterology
Volume134
Issue number7
DOIs
StatePublished - Jun 2008

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ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Apostolaki, M., Manoloukos, M., Roulis, M., Wurbel, M. A., Müller, W., Papadakis, K. A., Kontoyiannis, D. L., Malissen, B., & Kollias, G. (2008). Role of β7 Integrin and the Chemokine/Chemokine Receptor Pair CCL25/CCR9 in Modeled TNF-Dependent Crohn's Disease. Gastroenterology, 134(7), 2025-2035. https://doi.org/10.1053/j.gastro.2008.02.085