The intestinal epithelium constitutes an efficient barrier against the microbial flora. Here, we demonstrate an unexpected function of IL-33 as a regulator of epithelial barrier functions. Mice lacking IL-33 showed decreased Paneth cell numbers and lethal systemic infection in response to Salmonella typhimurium. IL-33 was produced upon microbial challenge by a distinct population of pericryptal fibroblasts neighboring the intestinal stem cell niche. IL-33 programmed the differentiation of epithelial progenitors toward secretory IEC including Paneth and goblet cells. Finally, IL-33 suppressed Notch signaling in epithelial cells and induced expression of transcription factors governing differentiation into secretory IEC. In summary, we demonstrate that gut pericryptal fibroblasts release IL-33 to translate bacterial infection into an epithelial response to promote antimicrobial defense.

Cytokines are small proteins that are secreted by a vast majority of cell types in the gut. They not only establish cell-to-cell interactions and facilitate cellular signaling, but also regulate both innate and adaptive immune responses, thereby playing a central role in genetic, inflammatory, and infectious diseases of the gut. Both, immune cells and gut epithelial cells, play important roles in intestinal disease development. The epithelium is located in between the mucosal immune system and the gut microbiome. It not only establishes an efficient barrier against gut microbes, but it also signals information from the gut lumen and its composition to the immune cell compartment. Communication across the epithelial cell layer also occurs in the other direction. Intestinal epithelial cells respond to immune cell cytokines and their response influences and shapes the microbial community within the gut lumen. Thus, the epithelium should be seen as a translator or a moderator between the microbiota and the mucosal immune system. Proper communication across the epithelium seems to be a key to gut homeostasis. Indeed, current genome-wide association studies for intestinal disorders have identified several disease susceptibility loci, which map cytokine signatures and their related signaling genes. A thorough understanding of this tightly regulated cytokine signaling network is crucial. The main objective of this review was to shed light on how cytokines can orchestrate epithelial functions such as proliferation, cell death, permeability, microbe interaction, and barrier maintenance, thereby safeguarding host health. In addition, cytokine-mediated therapy for inflammation and cancer are discussed.

Although induction of host cell death is a pivotal step during bacteria-induced gastroenteritis, the molecular regulation remains to be fully characterized. To expand our knowledge, we investigated the role of the central cell death regulator Caspase-8 in response to Salmonella Typhimurium. Here, we uncovered that intestinal salmonellosis was associated with strong upregulation of members of the host cell death machinery in intestinal epithelial cells (IECs) as an early event, suggesting that elimination of infected IECs represents a host defense strategy. Indeed, Casp8 mice displayed severe tissue damage and high lethality after infection. Additional deletion of Ripk3 or Mlkl rescued epithelial cell death and lethality of Casp8 mice, demonstrating the crucial role of Caspase-8 as a negative regulator of necroptosis. While Casp8Tnfr1 mice showed improved survival after infection, tissue destruction was similar to Casp8 mice, indicating that necroptosis partially depends on TNF-α signaling. Although there was no impairment in antimicrobial peptide secretion during the early phase of infection, functional Caspase-8 seems to be required to control pathogen colonization. Collectively, these results demonstrate that Caspase-8 is essential to prevent Salmonella Typhimurium induced enteritis and to ensure host survival by two different mechanisms: maintenance of intestinal barrier function and restriction of pathogen colonization.

Gastrointestinal infections with EHEC and EPEC are responsible for outbreaks of diarrheal diseases and represent a global health problem. Innate first-line-defense mechanisms such as production of mucus and antimicrobial peptides by intestinal epithelial cells are of utmost importance for host control of gastrointestinal infections. For the first time, we directly demonstrate a critical role for Stat3 activation in intestinal epithelial cells upon infection of mice with Citrobacter rodentium – a murine pathogen that mimics human infections with attaching and effacing Escherichia coli. C. rodentium induced transcription of IL-6 and IL-22 in gut samples of mice and was associated with activation of the transcription factor Stat3 in intestinal epithelial cells. C. rodentium infection induced expression of several antimicrobial peptides such as RegIIIγ and Pla2g2a in the intestine which was critically dependent on Stat3 activation. Consequently, mice with specific deletion of Stat3 in intestinal epithelial cells showed increased susceptibility to C. rodentium infection as indicated by high bacterial load, severe gut inflammation, pronounced intestinal epithelial cell death and dissemination of bacteria to distant organs. Together, our data implicate an essential role for Stat3 activation in intestinal epithelial cells during C. rodentium infection. Stat3 concerts the host response to bacterial infection by controlling bacterial growth and suppression of apoptosis to maintain intestinal epithelial barrier function.

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