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Régulation de la réponse inflammatoire intestinale par la fumée de cigarette : caractérisation des mécanismes cellulaires et moléculaires chez la souris

Abstract : Current hypothesis on the pathogenesis of inflammatory Bowel disease suggests that the disease development implicates a deregulated dialogue between the intestinal flora and components of both the innate and adaptive immune systems in genetically susceptible individuals and under the influence of environmental factors. To dateonly cigarette smoking and appendectomy have been shown to play a significant role. The effect of smoking appears to be ambivalent: it protects from ulcerative colitis (UC) but worsens Crohn’s disease (CD). Moreover, in CD it has been proposed that smoking might influence the disease location: CD patients who smoke were found to have a higher frequency of ileal disease and a lower frequency of colonic involvement. However, the molecular basis of the opposite effect of smoking in CD and UC still remain unexplained. Tobacco smoke molecules seem to possess various immunomodulatory properties but currently no clear conclusion can be drawn from in vitro and in vivo studies. To date, the influence of cigarette smoke on immune cells profile in the intestine remains unknown. The aim of this project was to characterize the effect of CS in murine models of intestinal inflammation, and the underlying mechanism implied in impact of CS in the colon and in the ileum at the cellular and molecular levels. To address this question, we developed a new model of exposition to CS using InExpose® exposure system (Scireq Inc) which allows us to accurately reproduce human smoking habits. We applied this protocol of exposure in two different animal models of intestinal inflammation: 1) the commonly used model of dextran sodium sulphate (DSS)-induced colitis and 2) the indomethacin-induced jejuno-ileitis model. C57BL/6 mice were pre-exposed to CS during two weeks before induction of one or another model of intestinal inflammationFirstly, we demonstrated in WT mice that CS exposure improved DSS-induced colitis but not indomethacin-induced ileitis. The colonic improvement was associated with a decrease in Th1/Th17 proinflammatory cytokines expression in the colon. This protection linked to CS exposure was specific to the colon since no modification of clinical and inflammatory parameters were observed in the jejuno-ileitis model.Secondly, we analyzed leukocyte population under CS exposure condition compared to control un-exposed mice. We showed by flow cytometry analysis that, in particular, iNKT cells were recruited by cigarette smoke in the colon and the liver (but not the small bowel) after CS exposure in non-inflammatory condition. To access the role of iNKT cells in CS dependant colonic protection, mice deficient in NKT cells (CD1dKO and J18KO mice) were exposed to the same protocols than WT mice. In NKT cell-deficient mice, CS exposure failed to improve colitis and to decrease the expression of proinflammatory cytokines. This implies that iNKT cells may be a major actor in the CS-dependent protection against DSS colitis. On the other hand, in NKT cell-deficient mice CS exposure seems to improve indomethacin-induced ileitis. This result indicates that iNKT cells could act differently according intestinal location or that the populations of iNKT in the different compartment of intestinal tracts may differ.In conclusion, this study demonstrated that mainstream CS exposure protects mice from experimental colitis but not from experimental ileitis. For the first time, we have identified iNKT cells as major player of the CS-dependent protection in colonic inflammation, whereas they might have a different role in the ileum. Therefore, our study contributes to better elucidate the impact of smoking, as a widespread environmental factor in IBD. Targeting iNKT cells would represent a novel therapeutic way. Design of new molecules acting on iNKT cells polarization could reproduce the effects of CS and allow decreasing the inflammation in the colon.
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Muriel Montbarbon. Régulation de la réponse inflammatoire intestinale par la fumée de cigarette : caractérisation des mécanismes cellulaires et moléculaires chez la souris. Médecine humaine et pathologie. Université du Droit et de la Santé - Lille II, 2013. Français. ⟨NNT : 2013LIL2S003⟩. ⟨tel-00951219⟩

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