Immunopathogenesis of experimental ulcerative colitis is mediated by eosinophil peroxidase.
The precise role that individual inflammatory cells and mediators play in the development of gastrointestinal (GI) dysfunction and extraintestinal clinical manifestations of ulcerative colitis (UC) is unknown. In this study, we have used a mouse model of UC to establish a central role for eotaxin and, in turn, eosinophils in the development of the immunopathogenesis of this disease. In this model the administration of dextran sodium sulfate (DSS) induces a prominent colonic eosinophilic inflammation and GI dysfunction (diarrhea with blood and shortening of the colon) that resembles UC in patients. GI dysfunction was associated with evidence of eosinophilic cytolytic degranulation and the release of eosinophil peroxidase (EPO) into the colon lumen. By using IL-5 or eotaxin-deficient mice, we show an important role for eotaxin in eosinophil recruitment into the colon during experimental UC. Furthermore, using EPO-deficient mice and an EPO inhibitor resorcinol we demonstrate that eosinophil-derived peroxidase is critical in the development of GI dysfunction in experimental UC. These findings provide direct evidence of a central role for eosinophils and EPO in GI dysfunction and potentially the immunopathogenesis of UC.
Forbes
Elizabeth
E
Allergy and Inflammation Research Group, Division of Molecular Bioscience, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
Murase
Tosei
T
Yang
Ming
M
Matthaei
Klaus I
KI
Lee
James J
JJ
Lee
Nancy A
NA
Foster
Paul S
PS
Hogan
Simon P
SP
D000818:Animals; D015550:Cell Degranulation / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002469:Cell Separation; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D003106:Colon / Q000473:pathology / Q000503:physiopathology; D016264:Dextran Sulfate / Q000008:administration & dosage; D003967:Diarrhea / Q000503:physiopathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D047209:Eosinophil Peroxidase; D004804:Eosinophils / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D006471:Gastrointestinal Hemorrhage / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D015848:Interleukin-5 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010544:Peroxidases / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012118:Resorcinols / Q000008:administration & dosage / Q000494:pharmacology
C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D004791:Enzyme Inhibitors; D015848:Interleukin-5; D012118:Resorcinols; D016264:Dextran Sulfate; D047209:Eosinophil Peroxidase; D010544:Peroxidases; C031389:resorcinol