Colonic Inflammation in Mice Is Improved by Cigarette Smoke through iNKT Cells Recruitment

Abstract

Cigarette smoke (CS) protects against intestinal inflammation during ulcerative colitis. Immunoregulatory mechanisms sustaining this effect remain unknown. The aim of this study was to assess the effects of CS on experimental colitis and to characterize the intestinal inflammatory response at the cellular and molecular levels. Using the InExpose® System, a smoking device accurately reproducing human smoking habit, we pre-exposed C57BL/6 mice for 2 weeks to CS, and then we induced colitis by administration of dextran sodium sulfate (DSS). This system allowed us to demonstrate that CS exposure improved colonic inflammation (significant decrease in clinical score, body weight loss and weight/length colonic ratio). This improvement was associated with a significant decrease in colonic proinflammatory Th1/Th17 cytokine expression, as compared to unexposed mice (TNF (p = 0.0169), IFNγ (p<0.0001), and IL-17 (p = 0.0008)). Smoke exposure also induced an increased expression of IL-10 mRNA (p = 0.0035) and a marked recruitment of iNKT (invariant Natural Killer T; CD45+ TCRβ+ CD1d tetramer+) cells in the colon of DSS-untreated mice. Demonstration of the role of iNKT cells in CS-dependent colitis improvement was performed using two different strains of NKT cells deficient mice. Indeed, in Jα18KO and CD1dKO animals, CS exposure failed to induce significant regulation of DSS-induced colitis both at the clinical and molecular levels. Thus, our study demonstrates that iNKT cells are pivotal actors in the CS-dependent protection of the colon. These results highlight the role of intestinal iNKT lymphocytes and their responsiveness to environmental stimuli. Targeting iNKT cells would represent a new therapeutic way for inflammatory bowel diseases.

Animal Inhalation Models to Investigate Modulation of Inflammatory Bowel Diseases

“…This tumour formation was associated with inhibition of cellular apoptosis and supported by increased angiogenesis. As a possible explanation for this discrepancy, this study used Balb/c mice while the protective effects of CS [22] were observed in C57BL/6 mice. Opposite responses in Balb/c mice, compared with C57BL/6 and other mouse strains, were also reported for other chemical inducers of IBD [67].…”

“…In contrast to its effects in CD rodent models, CS exposure for 2 weeks decreased UC-like inflammation in an acute DSS-induced colitis model in mice [22]. Montbarbon et al showed a significant decrease in macroscopic and histological colon damage, as well as in colonic proinflammatory cytokine expression, in DSS-exposed mice after CS inhalation.…”

“…In contrast, UC is considered a non-smokers' disease, with a significantly lower risk of disease development in current smokers. Despite the considerable research on smoking and IBD, the molecular mechanisms for CS-induced impacts on IBD development, as well as the specific CS components responsible, are not well understood [22].…”

The interaction between invariant Natural Killer T cells and the mucosal microbiota

“…28 In contrast, the lamina propria lymphocytes, which are scattered throughout the lamina propria underneath the epithelial layer, are more diverse in their cellular composition and resemble more those of other lymphatic organs. 29 iNKT cells can be detected in the mouse intestine at frequencies only slightly lower than in other peripheral organs, like the spleen and lymph nodes (stomach, 30 small intestine, [31][32][33] large intestine [33][34][35][36][37] ). Approximately 65% (BALB/c mice) to 85% (C57BL/6 mice) of intestinal iNKT cells are NKT1 cells, with the rest largely being NKT2 cells, and no differences in this distribution were noted for IELs versus lamina propria lymphocytes.…”

Exploring the microbiome in health and disease

“…164,199 IBD and the microbiome IBD is a group of disorders characterized by chronic inflammation of the gastrointestinal tract, of which the two main disease manifestations, ulcerative colitis (UC) and Crohn's disease (CD), each have distinctive clinical and pathological features. [200][201][202][203] Both CD and UC result from a complex interplay among environmental factors, genetics, and intestinal microbiota composition. 204,205 The important role of the microbiome in IBD pathogenesis has been elucidated by a study where germ-free animals showed less inflammation than controls in response to dextran sulfate sodium (DSS)-induced colitis.…”