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Expression of IRF8 in gastric epithelial cells confers protective innate immunity against Helicobacter pylori infection

ABSTRACT: The transcription factor IRF8 is expressed in many types of blood cells and plays critical roles in cellular differentiation and function. However, the role of IRF8 in nonhematopoietic systems remains poorly understood. In this study, we examined the role of IRF8 in gastric epithelial cells (GECs) and provided evidence that IRF8 is a transcriptional modulator of the gastric mucosa necessary for limiting H. pylori colonization. H. pylori infection significantly upregulated expression of IRF8, which in turn promoted IFN-γ expression by GECs. Mice deficient of IRF8 exhibited increased H. pylori colonization and aborted induction of mucosal IFN-γ. Genome-wide analyses of IFN-γ-treated GECs by ChIP-seq and RNA-seq led to identification of IRF8 target genes with many belonging to the IFN regulated gene family that was previously observed in immune cells. Our results identify the IRF8- IFN-γ circuit as a previously unrecognized gastric innate immune mechanism in defense against infection of H. pylori.

ORGANISM(S): Mus musculus

PROVIDER: GSE67476 | GEO | 2015/12/30

SECONDARY ACCESSION(S): PRJNA280046

REPOSITORIES: GEO

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Project description:Chronic infection with the bacterial pathogen Helicobacter pylori is a risk factor for the development of gastric cancer, yet remains asymptomatic in a majority of individuals. We report here that the C57Bl6 mouse model of experimental infection with the closely related H. felis recapitulates this wide range in host susceptibility. A majority of infected mice develop premalignant lesions such as gastric atrophy, compensatory epithelial hyperplasia and intestinal metaplasia, whereas a minority is completely protected from preneoplasia. Protection is associated with the failure to mount an IFN-gamma response to the infection and an associated high Helicobacter burden. We demonstrate that IFN-gamma is essential for clearance of Helicobacter, but also mediates the formation of preneoplastic lesions. We further provide evidence that IFN-gamma triggers a specific transcriptional program in murine gastric epithelial cells in vitro and in vivo, and induces their preferential transformation to the hyperplastic phenotype. In summary, our data suggest a dual role for IFN-gamma in Helicobacter pathogenesis that could provide an explanation for the differential susceptibility to H. pylori-induced gastric pathology in the human population. Keywords: response to in vitro stimulus / comparison of histopathological states We chose mice for gene expression profiling that following Helicobacter infection had (a) symptoms of gastritis, but no epithelial changes, (b) atrophic gastritis accompanied by corpus gland hyperplasia or (c) atrophic gastritis accompanied by intestinal metaplasia. An uninfected control group was also included in the analysis, as were two groups of mice that lacked mature T- and B-cells due to a deletion mutation in the rag1 gene (Rag-1-/-) and that were either experimentally infected or served as Rag-1-/- uninfected controls. To see the effects of IFNg on murine gastric epithelial cells we analysed an immortalized murine primary gastric epithelial cell line treated with three different concentrations of IFNg in comparison to an untreated control.

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Expression of IRF8 in gastric epithelial cells confers protective innate immunity against Helicobacter pylori infection

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