Date Published: June 14, 2019
Publisher: Public Library of Science
Author(s): Shaiya C. Robinson, Roopali Chaudhary, Rodrigo Jiménez-Saiz, Lyndsay G. A. Rayner, Luke Bayer, Manel Jordana, Juliet M. Daniel, Michael Koval.
Chronic intestinal inflammation contributes to pathologies such as inflammatory bowel disease (IBD) and colon cancer. While the precise etiology remains controversial, IBD is believed to manifest as a result of various factors. We previously reported that intestinal-specific overexpression of the transcription factor Kaiso results in an intestinal inflammatory response; however, the cause of this inflammation is unknown. To elucidate the underlying mechanism(s) of the Kaiso-mediated intestinal inflammatory phenotype, we evaluated two independent transgenic mouse lines that express varying levels of Kaiso (KaisoTg). Histological analyses of KaisoTg mice revealed intestinal damage including thickening of the mucosa, intestinal “lesions” and crypt abscesses, which are reminiscent of IBD pathology. Additionally, higher Kaiso levels induced intestinal neutrophilia as early as 12 weeks, which worsened as the mice aged. Notably, the Kaiso-induced intestinal inflammation correlated with a leaky intestinal barrier and mis-regulation of E-cadherin expression and localization. Interestingly, Kaiso overexpression resulted in reduced proliferation but enhanced migration of intestinal epithelial cells prior to the onset of inflammation. Collectively, these data suggest that Kaiso plays a role in regulating intestinal epithelial cell integrity and function, dysregulation of which contributes to a chronic inflammatory phenotype as mice age.
IBD refers to two intestinal disorders characterized by chronic inflammation: Crohn’s disease (CD), which affects both the small and large intestine in discontinuous patches of inflamed lesions, and ulcerative colitis (UC), which is restricted to the large intestine and presents as continuous regions of inflamed tissue [1–3]. Currently there is no cure for IBD, and both UC and CD are primarily managed by alleviation of the symptoms . Thus, a better understanding of the underlying molecular and/or genetic factors that contribute to IBD will facilitate the development of a curative treatment.
We previously demonstrated that intestinal-specific overexpression of the transcription factor Kaiso facilitates a chronic inflammatory phenotype in mice [14, 24], suggesting that Kaiso may be important in IBD pathogenesis. The observation that Kaiso expression is elevated in intestinal tissues of patients with CD (Fig 1) supported our hypothesis that Kaiso may potentiate inflammation and play a role in IBD disease progression. This necessitated a more detailed characterization of the mechanism(s) contributing to the Kaiso-induced inflammatory phenotype.
We report that Kaiso-induced intestinal inflammation involves perturbation of intestinal epithelial cell integrity, which is subsequently followed by a chronic inflammatory phenotype. We propose a working model of Kaiso-mediated inflammation, whereby reduced membrane localization of E-cadherin and abnormal epithelial renewal processes render the epithelium susceptible to inflammation and subsequent neutrophil recruitment. Together these perturbations ultimately contribute to increasingly severe chronic intestinal inflammation as KaisoTg mice age. Since the onset of neutrophil activity in KaisoTg mice varies depending on housing conditions, environmental factors (e.g. microbial load) may also influence the development of chronic inflammation in these mice, which is an avenue of future research (Fig 5). Nonetheless, the occurrence of spontaneous chronic inflammation observed in KaisoTg mice makes this mouse model a novel in vivo tool for IBD research.