Comparison of experimental mouse models of inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is multifactorial and involves immunological, environmental and genetic factors. Although there are no animal models that effectively mimic human IBD, experimental models allow us to analyze the mechanisms of chronic intestinal inflammation. IBD can be induced in mice by dextran sulfate sodium (DSS) or by a 2,4,6-trinitrobenzene sulfonic acid (TNBS)‑ethanol enema, which evoke immune responses and colitis. In this study, in order to compare the mechanisms of inflammatory response in mice, 3 distinct models of IBD were established: 2% TNBS-induced acute colitis, 4% DSS-induced acute colitis and 2% DSS-induced chronic colitis. In addition, to evaluate the effects of TNBS on inflammasome activation, we used caspase-1 knockout (KO) mice. Changes in both body weight and survival became prominent after day 1 in the 2% TNBS‑induced colitis model, and after day 5 in the 4% DSS-induced colitis model. The TNBS- and DSS-treated mice, but not the caspase-1 KO mice, showed a massive bowel edema and disruption of epithelial cells. The level of CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs) was increased in all tested tissues of the TNBS- and DSS-treated groups, apart from the basal membrane (BM) in the DSS-induced colitis groups and the lamina propria (LP) in the DSS-induced chronic colitis group. We further analyzed different subsets of CD4(+) T cells in LP and found that the levels of interferon (IFN)γ‑secreting (IFNγ(+)), IL-17‑secreting (IL-17(+)), but not those of IL-4-secreting (IL-4(+)) T cells increased upon treatment with TNBS or DSS. In addition, discrepancies between the histopathologies of wild-type and caspase-1 KO mice indicated that the pathogenesis of IBD may be associated with the inflammasome pathway responses mediated by caspase‑1 in TNBS‑induced colitis.

A miR-34a-Numb Feedforward Loop Triggered by Inflammation Regulates Asymmetric Stem Cell Division in Intestine and Colon Cancer

“…Tissues were then harvested and stained. Consistent with previous reports (Coste et al, 2007; Oh et al, 2014; Yan et al, 2009), DSS upregulated inflammatory factors TNFα, IL-1β and IL-6 in mouse intestine and colon inflammation (Figures S5D and S5E). Regeneration after DSS-induced tissue damage increased the number of Lgr5-GFP+ ISCs and Lgr5 and Ascl2 expression in the intestine and colon, which was further amplified by loss of miR-34a (Figures 7A–7F and S5F–S5G, 7A–7F).…”

Uncoupling Malt1 Threshold Function from Paracaspase Activity Results in Destructive Autoimmune Inflammation

“…In vitro colon cultures also showed spontaneous production of high IFNg, TNF, and IL-1b levels in Malt1 PM/À , but not Malt1 À/À or Malt +/À , samples ( Figure 1H). In a model of inflammatory bowel disease, we treated the animals with 3.5% dextran sodium sulfate (DSS) for 5 days to trigger intestinal epithelial damage (Oh et al, 2014). Malt1 PM/À mice developed a more rapid and aggravated inflammatory disease compared to control mice, with severe hemorrhagic diarrhea, increased weight loss ( Figure 1I), and an elevated histological severity score ( Figures 1J and 1K).…”

Oral Tolerance Induced by OVA Intake Ameliorates TNBS-Induced Colitis in Mice

“…These regulatory T cells generated in the intestine migrate to secondary lymphoid organs such as Peyer's patches and mesenteric lymph nodes, which inhibit the generation of nonspecific effector cells, by a mechanism known as bystander suppression [22,82]. In addition, the imbalance between proinflammatory and anti-inflammatory cytokines released by the intestinal mucosa determines the intensity and duration of the inflammatory response seen in experimental colitis [14,15,33,83–86]. …”

“…IL-17 together with IL-22 appear to be related to induction of colitis, since these cytokines initiate and amplify the local inflammatory signs and promote the activation of regulatory mechanisms directly against the cells of the intestinal epithelium [12,13]. In turn, IFN-γ induces the production of inflammatory cytokines by cells of the innate immune system, contributing to an increased tissue inflammation seen in colitis [4,12,14,15]. Therefore, modulation of Th17 and INF-γ-secreting cells may affect the inflammation in colitis.…”