Epithelial type I IFN receptor in the intestinal mucosa

Type I interferons (IFNs) are critical cytokines linking innate and adaptive immunity, which exert their function via the type I IFN receptor (IFNAR). The receptor consists of two chains, and in the absence of either, type I IFN signaling is abrogated. Beyond their antiviral function, type I IFNs regulate numerous physiological processes including inflammation, immunity, and cancer. Impaired ER (endoplasmic reticulum) stress mechanisms as reported by us, as well as impaired NFB signaling as reported by others, within intestinal epithelial cells have been linked to spontaneous intestinal inflammation and immune deviation, pointing toward a previously not appreciated critical role of the epithelium in regulating intestinal mucosal homeostasis. We hypothesize that type I IFN signaling in the intestinal epithelium is required for mucosal homeostasis, especially under conditions of microbial or inflammatory challenge to the mucosa. To test this hypothesis, we currently generate mice with a conditional deletion of Ifnar1 specifically in the intestinal epithelium. Using this mouse model we will investigate the role of IFNAR-signaling in regulating the inflammatory tone of the epithelium, and its role in barrier function. Furthermore, we will specifically address its effects on Paneth cells, especially with regard to their antimicrobial function. In addition, the effects of absence of Ifnar1 in the epithelium on dendritic cell and T cell function within the mucosa will be explored. Turning to models of an inflammatory and microbial challenge, we will explore the role of Ifnar1 in the epithelium during Citrobacter rodentium infection, as well as during dextran sodium sulfate (DSS) colitis, a barrier disruptive model of inflammatory bowel disease (IBD). Based on these latter results, we will further explore the role of Ifnar1 in the epithelium during the development of inflammation-associated cancer, using a carcinogen-augmented long-term DSS colitis model. These studies will substantially further our understanding of intestinal epithelial biology and investigate a critical group of mediators at the interface of innate and adaptive immunity. These studies might also have the prospect of pointing toward novel mucosal treatments, especially in IBD, with earlier trials of systemic administration of type I IFNs having already shown some promise in one form of IBD without understanding the mechanism behind it.

Our research group focuses on the inflammatory bowel diseases, which encompass Crohns disease and ulcerative colitis. These are life-long, debilitating conditions, which mostly manifest in young age and despite major advances in therapeutic avenues, they remain an area of substantial unmet medical. Our laboratorys goal is to unravel the mechanisms underlying these diseases to find more specific, more targeted, and more effective treatments.Genome-wide studies over the last few years have uncovered to genetic underpinning of complex immune-related disease to an unprecedented level. A major challenge is now to relate information on such genetic risk loci into a biological understanding of disease mechanisms. Genetics has been particularly successful in inflammatory bowel disease, hence providing a rich resource for directing mechanistic experiments to genetically affected pathways. In this project we focused on the IFNAR1 gene, which encodes a receptor for a particular type of cytokines, called type I interferons. These mediators are particularly important in viral, but also bacterial infections, and therefore we asked the important question on their role at the intestinal epithelium, the single cell layer that separates the bodys largest and most intensely populated habitat of microbial life (the microbiota) from the sterile environment of made of mammalian cells.Here we could show that in the absence of IFNAR1 in the epithelium, their specialised Paneth cells are affected, which secrete anti-bacterial peptides. As we could further show, this leads to a fundamental change in the composition of the microbial flora in the intestine. Interestingly, we discovered that the absence of IFNAR1 in the epithelium leads to the epitheliums increased regeneration. Unexpectedly, we found that this was not a direct effect within the intestinal epithelium caused by the genetic deletion, but required the altered microbiota to manifest. Importantly, this increased, microbiota-dependent regeneration of the IFNAR1-deficient epithelium would also lead to increased tumour formation in a model of colitis-associated cancer, which was again dependent on the altered microbial flora.Altogether, these data demonstrate that a host genetic defect may have profound effects on the microbiota, and the consequent altered composition of the microbiota is required for the manifestation of a phenotype in mammalian host cells. The intricate relationship of host immune system and the microbiota is thought to be at the mechanistic basis of inflammatory bowel disease, and our data on this genetic risk factor of Crohns disease lend further support on the critical importance of Paneth cells for the pathogenesis of the disease.