Community Research and Development Information Service - CORDIS


IL-22 AND IL-22BP Report Summary

Project ID: 337251
Funded under: FP7-IDEAS-ERC
Country: Germany

Mid-Term Report Summary - IL-22 AND IL-22BP (Identifying the immune and microbial network controlling the IL-22 – IL-22bp axis to open the doors for targeted therapies)

Chronic mucosal inflammation and tissue damage predispose to the development of colorectal cancer. One hypothesis is that the same factors important for wound healing, if left unchecked, also promote tumorigenesis. Tight control by a sensor of tissue damage should induce these factors to promote tissue repair, while limiting their activity to prevent development of cancer.
IL-22, a prototypical tissue repair factor, plays an important role in a wide variety of intestinal disease including infection, wound healing, colitis, and cancer. Using mouse models it was shown that IL-22 has protective and detrimental effects dependent on the milieu and disease suggesting that a tight regulation is required. Accordingly a spatial and temporal regulation of IL-22 is crucial. Hence, global administration or blockade of IL-22 is unlikely to be therapeutically beneficial. IL-22 expression is directly regulated, additionally a soluble IL-22 receptor (IL-22 binding protein; IL-22BP), can bind and neutralize IL-22. The aim of this project is to Identifying the immune and microbial network controlling the IL-22 – IL-22BP axis to open the doors for targeted therapies.
So far the relevance of the IL-22 – IL-22BP axis was studied mainly in mouse disease models. Thus in a first step we aimed to confirm the involvement of the IL-22 – IL-22BP axis in human diseases. Indeed we found that a dysregulated IL-22 – IL-22BP axis is associated with poor prognosis in colorectal cancer and therapy resistance in inflammatory bowel disease (IBD) in humans. Next we studied the cellular source of IL-22 and IL-22BP in colorectal cancer and IBD in humans and mouse models. We found that several immune cells can produce IL-22, but the most relevant source seems to be a specific CD4+ Thelper cell subset, namely TH17 cells. Consequently we are now focusing on mechanism regulating IL-22 production in this cell type. As for IL-22BP we found that dendritic cells (DCs) are the most relevant source in colorectal cancer, and we are thus focusing of the mechanism regulating IL-22BP in this immune cell. The inflammasome and IL-18 are suppressing IL-22BP production by DCs. The factors inducing IL-22BP are obviously crucial to develop new therapies but so far unknown. Indeed we have identified a candidate in this project, and we are now modulating the activity of this factor in mouse models as a therapy for colorectal cancer.
Several studies by other groups have shown that either specific commensal bacteria or specific metabolites of commensal bacteria, respectively, modulate components of the IL-22-IL22BP axis. These observations raised two important questions, which we have decided to focus on: first, how wide-spread are the proposed metabolic pathways within the tremendously diverse microbiota, and second, are the identified bacteria similarly able to modulate IL-22 and IL-22BP production from various cell types. To address the first question we are assembling a novel type of gene catalog of the microbiota encompassing millions of genes incorporating detailed taxonomic information, which is currently not available. Second, we are comparing modulation of IL-22 and IL-22BP production in innate and adaptive immune cells by a model bacterium using advanced gnotobiotic mouse models.
In conclusion our results so far have provide novel insights into the network between microflora, epithelium, and immune system regulating tissue regeneration and tumor development. We are now aiming to understand the underlying mechanism. Furthermore were are testing factors modulating the IL-22 – IL-22BP axis as therapies for a wide variety of intestinal diseases, such as infection, colon cancer, IBD, or wound healing in mouse models.

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