Role of β7 integrin and the chemokine/chemokine receptor pair CCL25/CCR9 in modeled TNF-dependent Crohn's disease

Background & Aims: In the present work, we address the requirement for intestinal-specific homing molecules, the chemokine/chemokine receptor pair CCL25/CCR9 and beta 7 integrin, in the pathogenesis of the CD8(+) T cell-dependent Tnf(Delta ARE) 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, alpha 4 beta 7, and alpha E beta 7 integrin. The functional significance of CCL25/CCR9 and beta 7 integrin in inflammatory lymphocyte recruitment and intestinal disease development was assessed in Tnf(Delta ARE) mice genetically lacking these molecules. Results: Intestinal inflammation in the Tnf(Delta ARE) mice is associated with early reduction of CD8 alpha alpha-expressing intraepithelial lymphocytes, decreased T helper cell 1 and increased T helper cell 17 responses by LP CD4(+) lymphocytes, increased alpha E beta 7 integrin expression in peripheral activated/memory intestinal-homing CD8 alpha beta lymphocytes, and predominance of tumor necrosis factor/interferon-gamma-producing CD8 alpha beta 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, CD8 alpha beta lymphocyte recruitment in the intestinal epithelium and inflammatory infiltration in the LP are not impaired in CCR9- or CCL25-deficient Tnf(Delta ARE) mice. In contrast, genetic ablation of beta 7 integrin results in complete amelioration of intestinal pathology. Conclusions: Our findings demonstrate that development of intestinal inflammation in the Tnf(Delta ARE) mice is critically dependent on beta 7 integrin-mediated T-lymphocyte recruitment, whereas the function of the CCL25/CCR9 axis appears dispensable in this model.