Role of beta7 integrin and the chemokine/chemokine receptor pair CCL25/CCR9 in modeled TNF-dependent Crohn's disease.
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.
Apostolaki
Maria
M
Institute of Immunology, Biomedical Sciences Research Center Alexander Fleming, Vari, Greece.
Manoloukos
Menelaos
M
Roulis
Manolis
M
Wurbel
Marc-André
MA
Müller
Werner
W
Papadakis
Konstantinos A
KA
Kontoyiannis
Dimitris L
DL
Malissen
Bernard
B
Kollias
George
G
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*
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