Intestinal-Specific TNFα Overexpression Induces Crohn's-Like Ileitis in Mice

Background and Aim: Human and animal studies have clearly established tumor necrosis factor (TNF)alpha as an important mediator of Crohn's disease pathogenesis. However, whether systemic or only local TNF alpha overproduction is required for the development of chronic intestinal inflammation and Crohn's disease remains unclear. The aim of this study was to assess the contribution of intestinal epithelial-derived TNF alpha to the development of murine Crohn's-like ileitis. Methods: We adapted the well-established TNF Delta ARE/+ mouse model of Crohn's disease (which systemically overexpresses TNF alpha) to generate a homozygous mutant strain that overexpress TNF alpha only within the intestinal epithelium. Intestinal-specific TNFi Delta ARE/i Delta ARE mice were examined for histopathological signs of gut inflammation and extraintestinal manifestations of Crohn's disease. The mucosal immune phenotype was characterized, and the contribution of specific lymphocyte populations to the pathogenesis of TNFi Delta ARE/i Delta ARE ileitis was assessed. Results: TNFi Delta ARE/i Delta ARE mice had increased mucosal and systemic TNF alpha levels compared to wild-type controls (P<0.001), as well as severe chronic ileitis with increased neutrophil infiltration and villous distortion, but no extraintestinal manifestations (P<0.001 vs. wild- type controls). The gut mucosal lymphocytic compartment was also expanded in TNFi Delta ARE/i Delta ARE mice (P<0.05), consisting of activated CD69(+) and CD4(+)CD62L(-) lymphocytes (P<0.05). FasL expression was significantly elevated in the mesenteric lymph nodes of TNFi Delta ARE/i Delta ARE mice (P<0.05). Adoptive transfer of mucosal TNFi Delta ARE/i Delta ARE lymphocytes resulted in ileitis in immunologically naive severe combined immunodeficiency recipients (P<0.05 vs. wild-type controls), indicating an effector phenotype that was associated with increased production of both Th1 (IFN gamma) and Th2 (IL-5, IL-13) cytokines. Conclusion: Intestinal epithelial-derived TNF alpha is sufficient for the induction of Crohn's-like ileitis, but not for the occurrence of extraintestinal manifestations, in TNFi Delta ARE/i Delta ARE mice. These effects were associated with generation of effector lymphocytes within the intestinal mucosa and dysregulated apoptosis. Thus, targeted intestinal blockade of TNF alpha may provide an effective means to neutralize gut-derived TNF alpha with reduced side effects.