Type-III IFN signalling through PKR is required for RipK3 activation in intestinal epithelial cells.

Interferons (IFNs) play a critical role in the antimicrobial host defense. Despite the fact that IFN-λ, a type-III IFN, has been shown to predominantly act on mucosal organs, in vivo studies have failed to elucidate a specific, nonredundant function. Here we investigated the influence of type III IFNs on intestinal homeostasis.  

IFN administration induced increased epithelial shedding which was dependent on caspase-8 activation in wildtype animals. Mice deficient for caspase-8 in intestinal epithelial cells (Caspase-8^ΔIEC mice) showed excessive cell death and villous atrophy associated with high mortality in response to IFN. Disruption of barrier function required RipK3, since RipK3-/-xCaspase-8^ΔIEC animals were protected from IFN induced epithelial cell death, indicating that this form of cell death is due to RipK3-mediated necroptosis. Interestingly IFN-λ induced necroptosis occurs independently of Tnf signalling and is instead mediated via the Stat1-PKR (RNA-responsive protein kinase) pathway. Moreover we could identify that under steady state conditions and after viral infection, IFN-λ is mainly expressed by intestinal epithelial cells and is transcriptionally regulated by the intestinal microbiota, since germ free animals have significantly lower IFN-λ mRNA levels. Taken together, our data reveal how IL28 mediates acute inflammation through Stat1/PKR mediated Rip dependent cell death.