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Identifying the immune and microbial network controlling the IL-22 – IL-22bp axis to open the doors for targeted therapies

Final 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 predisposes 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 diseases 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. 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 was to identify the immune and microbial network controlling the IL-22 – IL-22BP axis to open the doors for targeted therapies.
Previously the relevance of the IL-22 – IL-22BP axis had been studied mainly in mouse disease models. Thus, 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 patients with colorectal cancer (CRC) and therapy resistance in patients with inflammatory bowel disease (IBD). 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. However, the most relevant source of pro-tumorigenic IL-22 seemed to be a specific CD4+ Thelper cell subset, namely TH17 cells, and we furthermore described the mechanism regulating IL-22 production by this T-cell subset. As for IL-22BP we found that dendritic cells (DCs) and CD4+ T cells are the key sources. We furthermore identified the mechanisms regulating IL-22BP production by DCs. Despite these studies key aspects regarding IL-22BP producing T-cell remained unknown and could not be answered due to technical limitations. We have thus generated an IL-22BP reporter/ fate mapping mouse model which will allow us to study the functional and molecular heterogeneity as well as the transcriptional regulatory network controlling IL-22BP.
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 assembled a novel type of gene catalog of the microbiota encompassing millions of genes incorporating detailed taxonomic information, which was not available before. Second, we compared 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 have provided novel insights into the network between microflora, epithelium, and immune system regulating tissue regeneration and tumor development. Furthermore we have identified the pathways controlling IL-22BP expression by DCs. These findings might build the basis to therapeutically modulate the IL-22 – IL-22BP axis as in potentially a wide variety of intestinal diseases, such as infection, colon cancer, IBD, or wound healing.