IL-20-mediated suppression of pro-inflammatory epithelial STAT2 signaling in mucosal healing and inflammatory bowel disease

• Applicants: Dr. Mircea Teodor Chiriac; Professor Dr. Markus F. Neurath
• Subject Area: Gastroenterology
• Term: since 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 326689882

Over 400.000 German citizens suffer from inflammatory bowel diseases (IBD), a group of chronic, relapsing and progressive disorders in which the intestinal homeostasis has been compromised by overreacting immune responses to intestinal flora in genetically susceptible individuals. It is currently believed that microbiota initiate a local immune response that induces the release of pro-inflammatory cytokines including type I interferons (IFN) which can trigger epithelial cell death by activating STAT2. Increased epithelial cell death is associated with impaired barrier function which allows the translocation of luminal microbial contents into the underlying lamina propria, thus amplifying inflammation. Anti-inflammatory cytokines that are also secreted in this context coordinate the resolution of inflammation and tissue repair. IL-20 has been previously shown to play a critical role during tissue remodeling in psoriasis but its role in IBD is unknown. Our results of the first funding period, demonstrated that Stat2-/- mice were more resistant to inflammation and showed faster recovery compared to wild type controls. In contrast, two newly generated strains lacking IL-20 signaling i.e. Il20-/- and Il20rb-/- mice showed increased susceptibility. In IBD patients, STAT2 and IL-20 levels correlated with disease activity. Taken together, our preliminary results strengthened our novel scenario in which IL-20 antagonizes the IFN-STAT2 pathway during intestinal inflammation thus emerging as a promising compensatory mechanism involved in gut homeostasis. Taking advantage of material from IBD patients and two novel conditional knock-out strains specifically created for the second funding period i.e. Stat2fl/fl and Il20fl/fl we aim to address the following objectives in a cell-specific manner: 1) dissection of the molecular interactions involved in the type I IFN-STAT2-induced intestinal inflammation; 2) study the cell-specific mechanisms by which IL-20 blocks the IFN-STAT2 axis to initiate the resolution of inflammation and the reestablishment of the barrier function. To extend our analysis we will use three-dimensional organotypic cultures from the small and the large intestine of mice as well as IBD patients with different disease stages/therapy schemes. For deep profile phenotyping we will interrogate formalin-fixed paraffin-embedded human tissue arrays in the spatial context using Maxpar metal-conjugated antibodies and Imaging Mass Cytometry which enables a multi-parameter analysis of tissue landscapes. We will prospectively monitor IL-20 biology in patients included in our clinical trials to spot out correlations between IL-20 levels and responsiveness to one or the other therapies. We strongly believe that by the end of the second funding period our results will significantly aid to the understanding of the resolution phase of gut inflammation which should create a solid basis for the development of innovative therapeutic solutions for IBD patients.

• DFG Programme: Research Grants