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078 CONSEQUENCES OF TOLL-LIKE RECEPTOR 2 DEFICIENCY AND AGING IN A MURINE MODEL OF COLITIS EJ Albert1,2, J Duplisea3, JS Marshall1,2,3 The ability of Toll-like receptors (TLR) to modulate inflammatory responses to the indigenous intestinal microflora has been implicated in inflammatory bowel disease (IBD). Aging is also associated with factors potentially affecting IBD such as a decline in aspects of immune function and a higher susceptibility to bacterial infection among the elderly. This study aimed to determine the role of TLR2 in modulating inflammation in the dextran sodium sulphate (DSS) model of intestinal inflammation, in both young and aged mice.
1Dalhousie Inflammation Group; Departments of 2Pathology and 3Microbiology & Immunology, Dalhousie University, Halifax, Nova Scotia
Male C57Bl/6 and TLR2-deficient mice (TLR2-KO), 8-10 weeks (young) and greater than 60 weeks of age (aged), were treated with 3% (wt/vol) DSS for 5 days followed by 5 days of normal food and water. Samples from the cecum and mid-colon were removed on days 5 and 10 and analyzed to determine cytokine profiles and histological scores.
Young and aged TLR2-KO mice had increased histological scores, reduced colon lengths and had lost significantly more weight than matched C57Bl/6 mice by day 10 (p<0.001). Untreated aged TLR2-KO mice showed reduced levels of colonic IFN-gamma (p<0.01) and IL-10 (p<0.001) compared to younger TLR2-KO mice. On day 10 there were significant increases in colon IFN-gamma levels in both young C57Bl/6 and TLR2-KO mice (p<0.001), whereas levels remained unchanged in both aged C57Bl/6 and aged TLR2-KO mice. Colonic IL-10 levels were significantly reduced in young C57Bl/6 (p<0.001) and TLR2-KO mice (p<0.05) at day 10 while they increased from baseline by day 10 in aged TLR2-KO mice (p<0.001). Histological analyses of tissues from day 10 revealed that young and aged TLR2-KO mice had more severe mucosal ulceration, an increased presence of inflammatory cells, and an impaired ability to facilitate mucosal repair. Further examination revealed significantly fewer eosinophils in both cecal (p<0.01) and colonic (p<0.01) tissue of young TLR2-KO mice on day 10, accompanied by lower levels of both IL-5 and eotaxin in these tissues.
This study indicates an important role for TLR2 in modulating inflammation during intestinal damage regardless of age, although there are substantial age-related changes in cytokine responses.
Supported by the Nova Scotia Health Research Foundation and by the Crohn's and the Colitis Foundation of Canada