P059. Cigarette smoke improves colonic inflammation through NKT cells activation in mice
M. Montbarbon1, M. Pichavant2, A. Langlois1, E. Erdual1, S. Dharancy1, L. Dubuquoy1, F. Trottein2, P. Desreumaux1, P. Gosset2, B. Bertin1
1Inserm, U995, Lille, France; 2Inserm, U1019, Lille, France
Background: Epidemiological studies strongly linked cigarette smoking and inflammatory bowel diseases (IBD). Smoking protects against ulcerative colitis, but increases the risk of developing Crohn's disease. It would be important to gain insight in the mechanism of these dual effects of smoking. Moreover, the overall immunomodulatory effects of the components of cigarette smoke (CS) on the intestinal inflammatory cascade are poorly known.
Our aim is to characterize the intestinal inflammatory response at the cellular and molecular levels using murine models of colonic and ileal inflammation exposed to CS.
Methods: C57BL/6 mice and KO mice were exposed during 3 weeks to CS of 5 cigarettes/days using the InExpose® exposure system (Scireq Inc). Colitis was induced with 2.5% DSS and ileitis was induced with indomethacin (100 mg/kg s.c.). The intestinal inflammation was assessed at the clinical, cellular and molecular levels.
Results: In wild-type mice, CS exposure improved DSS-induced colonic inflammation (improvement of body weight loss (n = 30; p < 0.0001), clinical score (p = 0.01) and weight/length colonic ratio (p < 0.0001)). This was associated with a significant decrease in colonic TNF (p = 0.0169), IFN γ (p < 0.0001) and IL‑22 (p = 0.0016) mRNA expression along with a decreased of Natural Killer cells (NK1.1+ CD5−) recruitment in the colon. CS exposure alone induced colonic expression of IL‑10 mRNA (p = 0.0035) as well as the recruitment of activated NKT (Natural Killer T) cells (TCRb+ CD1d tetramer+ CD25+) in the colonic lamina propria, suggesting the implication of NKT cells in CS protective effect. In NKT deficient mice (Ja18KO and CD1dKO), CS exposure failed to induce significant regulation of colonic inflammation. Restoration of the inflammation regulation in Ja18KO with adoptive transfer of CS exposed NKT cells is currently under investigation. In contrast to the colon, CS did not lead to major modification of intestinal inflammatory response in indomethacin-induced ileitis. We only detected a significant decrease of injured area without any decrease of their numbers nor decrease of expression of inflammatory markers.
Conclusions: Our study describes the intestinal cytokines and leukocytes associated with CS exposure. Our results show for the first time that the protecting effect of CS on intestinal inflammation depends of NKT cells. Identifying the molecular mechanism(s) involved in the activation of protective NKT cells might help to develop new therapeutic approaches for IBD.