Abstract
BackgroundHnf4α, an epithelial specific transcriptional regulator, is decreased in inflammatory bowel disease and protects against chemically-induced colitis in mice. However, the precise role of this factor in maintaining normal inflammatory homeostasis of the intestine remains unclear. The aim of this study was to evaluate the sole role of epithelial Hnf4α in the maintenance of gut inflammatory homeostasis in mice.Methodology/Principal FindingsWe show here that specific epithelial deletion of Hnf4α in mice causes spontaneous chronic intestinal inflammation leading to focal areas of crypt dropout, increased cytokines and chemokines secretion, immune cell infiltrates and crypt hyperplasia. A gene profiling analysis in diseased Hnf4α null colon confirms profound genetic changes in cell death and proliferative behaviour related to cancer. Among the genes involved in the immune protection through epithelial barrier function, we identify the ion transporter claudin-15 to be down-modulated early in the colon of Hnf4α mutants. This coincides with a significant decrease of mucosal ion transport but not of barrier permeability in young animals prior to the manifestation of the disease. We confirm that claudin-15 is a direct Hnf4α gene target in the intestinal epithelial context and is down-modulated in mouse experimental colitis and inflammatory bowel disease.ConclusionOur results highlight the critical role of Hnf4α to maintain intestinal inflammatory homeostasis during mouse adult life and uncover a novel function for Hnf4α in the regulation of claudin-15 expression. This establishes Hnf4α as a mediator of ion epithelial transport, an important process for the maintenance of gut inflammatory homeostasis.
Highlights
Hepatocyte-nuclear-factor-4a (Hnf4a) was originally identified as an endoderm specific transcriptional regulator detectable in the liver, pancreas and intestine, essential for embryonic development [1]
Our results highlight the critical role of Hnf4a to maintain intestinal inflammatory homeostasis during mouse adult life and uncover a novel function for Hnf4a in the regulation of claudin-15 expression
We propose that the loss of mucosal homeostasis is initiated by an early reduction of mucosal ion transport, which was not associated with a significant change of barrier permeability
Summary
Hepatocyte-nuclear-factor-4a (Hnf4a) was originally identified as an endoderm specific transcriptional regulator detectable in the liver, pancreas and intestine, essential for embryonic development [1]. In vitro studies suggest that it stimulates intestinal epithelial cell differentiation, resulting in the formation of a tight epithelial barrier [5] These features are central to the differentiated epithelium to ensure nutrient metabolism [6] and barrier protection against pathogens [7]. Another fundamental characteristic of the epithelial barrier is to regulate appropriate ion selectivity, for which impairment contributes to the manifestation of inflammatory bowel disease (IBD) [8,9]. Hnf4a, an epithelial specific transcriptional regulator, is decreased in inflammatory bowel disease and protects against chemically-induced colitis in mice. The aim of this study was to evaluate the sole role of epithelial Hnf4a in the maintenance of gut inflammatory homeostasis in mice
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