Role of IFN-L in IBD: impact on the regenerative capacity of intestinal epithelial cells. – INTERMICI

In this proposal, we will determine the role of the mucosal cytokine Interferon lambda IFN-? in controlling the capacity of intestinal epithelial cells to orchestrate tissue regeneration in IBD and the microbial determinants and cellular sources responsible for IFN-? expression in the gut in health and disease.
IBD is indeed a multifactorial disease characterized by a dysregulated immune response to environmental factors in the gut, which results in extensive inflammatory damage to the intestinal mucosa. The resulting inflammatory wounds cause a breach in barrier integrity, which triggers repair mechanisms involving the epithelium necessary to return to homeostasis.
Indeed, a priority in IBD treatment is promoting mucosal healing and the restoration of epithelial cell function. Therefore, mucosal healing mechanisms are increasingly studied in preclinical models of IBD and in in vitro models of intestinal epithelial cells (IECs) to develop targeted therapeutics. While IECs are key players in epithelial restitution, this process is also heavily influenced by crosstalk with the immune system. We find that IFN-? plays a pivotal role in the context of mucosal healing as this cytokine is known to be an important regulator of mucosal homeostasis. While IFN-? induces similar antiviral responses to type I interferons, thanks to the expression of its receptor (IFNLR1) only in epithelial cells and neutrophils, IFN-? can both protect mucosae from viruses and curb inflammation by inhibiting neutrophil functions.
IFN-? has been most studied for its direct antiviral action in the gut, but recent studies have uncovered its importance in curbing excessive barrier damage in acute models of intestinal inflammation in the absence of an active viral infection, where basal levels of IFN-? are produced in response to the intestinal microbiome. The nature of the microbial stimuli that induce IFN-? and the cell types responsible for its production in the gut are unknown, but recently basal IFN-? levels have been linked with the colonization of enteric viruses. These observations support clinical studies that document elevated IFN-? transcript levels in ileal biopsies from IBD patients and show that the intestinal virome is dysregulated in the stool of IBD patients.
In mouse models of IBD, we have demonstrated that IFN-? down-modulates intestinal inflammation by acting on neutrophils and inhibiting their capacity to mediate tissue damage. However, while IFN-? is believed to have evolved to protect the intestinal mucosa from viral infection while maintaining barrier integrity, the significance of IFN-? induced by the intestinal microbiome in influencing tissue repair after acute inflammatory pathologies is unclear. Based on our recent work showing that IFN-? can interfere with repair by inhibiting epithelial cell proliferation in a model of prolonged viral infection in the lung, we hypothesize that IFN-? is produced in the gut in response to commensal viruses upon barrier breakage and acts on IECs to negatively influence their capacity to orchestrate tissue repair. In support of this hypothesis, we generated preliminary data showing that: i) both administered end endogenous IFN-? impairs repair in mouse models of IBD, ii) IFN-? acts directly on epithelial cells and inhibits repair by curbing proliferation and promoting cell death, and iii) IFN-? is produced in the colon and small intestine (s.i.) after barrier breakage in response to commensal viruses.
We thus propose the following specific aims:
Aim1: To define the relevance of IFN-? signaling in epithelial cells in controlling tissue restitution.
Aim2: To identify the microbial stimuli that govern tonic IFN-? production in the gut.
Aim3: To establish the host processes responsible for IFN-? production in the intestine in health and disease.
Our discoveries will contribute to the design of therapeutic interventions for modulating IFN-? production and/or signaling in IECs during mucosal repair.