Final Report Summary - EPINFLAM (Epithelial cells in inflammation)
Epithelial tissues such as the gut and the skin form interfaces between the body and the environment and provide important structural and immunological barriers against injury and infection. Barrier tissues are colonised with rich commensal microbial communities that provide many beneficial functions to the host but can also cause inflammation and disease by activating the immune system. Mechanisms that prevent immune responses against commensal microbes are important for the maintenance of immune homeostasis in barrier tissues and the prevention of chronic inflammatory diseases such as inflammatory bowel disease (IBD) and psoriasis. The main aim of Epinflam was to understand the role of epithelial cells in the regulation of tissue homeostasis and inflammation in barrier tissues with particular focus in the gastrointestinal tract. Our results identified key mechanisms by which epithelial cells maintain healthy immune homeostasis and prevent inflammatory responses in barrier tissues. We found that death of epithelial cells is a potent trigger of inflammation in vivo and that mechanisms regulating cell survival play a key role in suppressing bacteria-induced inflammatory responses in the gut. Our findings provided evidence that not only inflammatory types of cell death such as necroptosis, but also apoptosis, which is generally considered a non-immunogenic cell death process, could trigger inflammation, suggesting that the immunoregulatory properties of different types of cell death are dependent on tissue- and stimulus-specific responses. Furthermore, our work within Epinflam unravelled key molecular mechanisms that act in epithelial cells to maintain immune homeostasis in barrier tissues. We found that the primary function of the IKK/NF-kB signalling pathway in epithelial cells is to maintain barrier integrity by preventing cell death. Moreover, we identified receptor interacting protein kinase 1 (RIPK1) as a critical regulator of epithelial homeostasis, exerting both kinase-independent and kinase-dependent functions that are critical for the maintenance of barrier integrity. These results revealed that a balanced interplay between IKK/NF-kB and RIPK1 signalling is critical to preserve epithelial cell viability and barrier integrity at the interface between the commensal microbiota and the mucosal immune system. Our findings also provide an alternative mechanism explaining the potent pathogenic function of TNF in chronic inflammatory diseases such as IBD, suggesting that TNF-induced cell death could contribute to disease pathogenesis. Collectively, the findings obtained within Epinflam identified epithelial cell death as a potent trigger of inflammation in barrier tissues and suggest that therapeutic approaches targeting cell death, such as RIPK1 kinase inhibitors, could be effective for the treatment of chronic inflammatory diseases.