IL-33 Drives Eosinophil Infiltration and Pathogenic Type 2 Helper T-Cell Immune Responses Leading to Chronic Experimental Ileitis

Abstract

Although a clear association has been established between IL-33 and inflammatory bowel disease, mechanistic studies to date, primarily using acute murine models of colitis, have yielded contradicting results, demonstrating both pathogenic and protective roles. We used a well-characterized, spontaneous model of inflammatory bowel disease [ie, SAMP1/YitFc (SAMP) mice] to investigate the role of IL-33 during chronic intestinal inflammation. Our results showed marked eosinophil infiltration into the gut mucosa with increased levels of eotaxins and type 2 helper T-cell (Th2) cytokines as disease progressed and became more severe, which could be reversed upon either eosinophil depletion or blockade of IL-33 signaling. Exogenous IL-33 administration recapitulated these effects in ilea of uninflamed (parental) control AKR/J mice. Human data supported these findings, showing colocalization and up-regulation of IL-33 and eosinophils in the colonic mucosa of inflammatory bowel disease patients versus noninflamed controls. Finally, colonization of commensal flora by fecal material transplantation into germ-free SAMP and the presence of the gut microbiome induced IL-33, subsequent eosinophil infiltration, and mounting of Th2 immune responses, leading to exacerbation of chronic intestinal inflammation characteristic of SAMP mice. These data demonstrate a pathogenic role for IL-33-mediated eosinophilia and activation of Th2 immunity in chronic intestinal inflammation that is dependent on the gut microbiome. Targeting IL-33 may represent a novel therapeutic approach to treat patients with inflammatory bowel disease.

A signalling cascade of IL-33 to IL-13 regulates metaplasia in the mouse stomach

“…Efforts to circumvent metaplasia development through manipulation of EGF ligands/receptors (Areg [34], EGFR [34, 35]), endocrine pathways (gastrin [10, 36], histamine [37]) and cytokines (IFNγ [38, 39, 40], IL–11 [41]) have yet to identify factor(s) necessary for the induction of metaplasia in response to parietal cell loss in either an acute drug induced system or chronic Helicobacter infection. Previous studies found that administration of IL-33 is sufficient to induce hypertrophy and mucous metaplasia in the airway, stomach, and intestine through the induction Th2 cytokines and infiltration of myeloid cells and eosinophils [20, 21, 42, 43, 44, 45]. Furthermore, it is well-established that IL-33 signaling results in up-regulation of the expression of IL-13, which is required for the development of mucous metaplasia in the airway allergic response.…”

Uncovering Pathogenic Mechanisms of Inflammatory Bowel Disease Using Mouse Models of Crohn’s Disease–Like Ileitis: What is the Right Model?

“…However, Bamias et al 25 showed that germ-free SAMP1/YitFc mice develop ileitis with varying degrees of severity, the majority showing a milder form of the disease, confirming the importance of the gut microbiome as a modulating factor of chronic intestinal inflammation. The absence of a commensal flora appears preferentially to impact the Th2-driven chronic phase of SAMP1/YitFc ileitis, with significantly reduced levels of IL33, and downstream IL5 and IL13 at 13 weeks of age, and decreased chronic inflammatory scores through 30 weeks of age, providing further evidence that interactions with the gut microbiome drive production of Th2 cytokine production during the chronic phase of SAMP1/YitFc ileitis 26, 73…”

Recent Advances: The Imbalance of Cytokines in the Pathogenesis of Inflammatory Bowel Disease

“…In DSS-induced chronic colitis, IL-33 ameliorates the intestinal inflammation through suppressing Th1 and Th17 responses [82]. However, in SAMP1/YitFc spontaneous chronic murine colitis model, IL-33 administration worsens the chronic intestinal inflammation by enhancing eosinophil infiltration and increasing pathogenic Th2 response [83]; these effects can be reversed by blockade of IL-33 signaling or depletion of eosinophils and required gut microbiomes [83, 84]. These animal findings indicate that IL-33 may confer protection from injury or lead to inflammation although the behind mechanisms remain largely undefined.…”