BACKGROUND & AIMS: 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.
BACKGROUND & AIMS: 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: Wei-Jian Pan; Kathleen Köck; William A Rees; Barbara A Sullivan; Christine M Evangelista; Mark Yen; Jane M Andrews; Graham L Radford-Smith; Peter J Prince; Kaz O Reynhardt; David R Doherty; Sonal K Patel; Christine D Krill; Kefei Zhou; Jing Shen; Lynn E Smith; Jason M Gow; Jonathan Lee; Anthony M Treacy; Zhigang Yu; Virginia M Platt; Dominic C Borie Journal: Br J Clin Pharmacol Date: 2014-12 Impact factor: 4.335
Authors: Isaac Rosado-Sánchez; Amaia González-Magaña; María M Pozo-Balado; Inés Herrero-Fernández; María J Polaino; María M Rodríguez-Méndez; María Francisca González-Escribano; Manuel Leal; Yolanda M Pacheco Journal: Lab Invest Date: 2018-01-18 Impact factor: 5.662
Authors: W J Pan; H Hsu; W A Rees; S P Lear; F Lee; I N Foltz; P Rathanaswami; K Manchulenko; B M Chan; M Zhang; X Z Xia; S K Patel; P J Prince; D R Doherty; C M Sheckler; K O Reynhardt; C D Krill; B J Harder; J A Wisler; J L Brandvig; J L Lynch; A A Anderson; L C Wienkers; D C Borie Journal: Br J Pharmacol Date: 2013-05 Impact factor: 8.739
Authors: A Viejo-Borbolla; A P Martin; L R Muniz; L Shang; F Marchesi; N Thirunarayanan; N Harpaz; R A Garcia; M Apostolaki; G C Furtado; L Mayer; G Kollias; A Alcami; S A Lira Journal: Mucosal Immunol Date: 2010-07-21 Impact factor: 7.313