Periodic Reporting for period 2 - REpAIR (Spatio-Temporal Regulation of Inflammation and Tissue Regeneration: Studying the immune system - tissue - microbiota communication to develop targeted therapies for immune-mediated diseases and cancer)
Okres sprawozdawczy: 2022-04-01 do 2023-09-30
A physiological tissue regeneration depends on fine-tuned interaction between the immune system, the tissue, and the microbiota. However, the complex communication between these three components and the molecules that mediate it is unclear. Understanding this is fundamental to prevent and treat immune-mediated diseases and cancer. Interleukin-22 (IL-22) is one key orchestrator of this communication: It is produced by immune cells and by acting on intestinal epithelial cells, it modulates the composition of the microbiota and promotes tissue regeneration. However, IL-22 can also promote both chronic inflammation and cancer. Of note, there is an endogenous inhibitor of IL-22, namely IL-22 binding protein (IL-22BP), which blocks IL-22 activity.
Our objectives are to study IL-22 and IL-22BP producing immune cells in terms of: their location, their functional and molecular heterogeneity, their origin and fate; and the role of the microbiota in regulating them. To this end, we will use new transgenic and gnotobiotic mouse models, single cell RNA sequencing and human samples. We will start to study the IL-22 - IL-22BP axis, in order to understand how the complex interactions between the immune system, the tissue, and the microbiota leads to either physiological or pathological tissue regeneration. On the basis of these data, we aim to go beyond IL-22 – IL-22BP and to identify general mechanisms regulating inflammation and cancer. This will finally provide the basis for therapies controlling inflammation and tissue regeneration in a spatio-temporal manner.
Regarding the intestinal microbiota in regulating IL-22, we found that segmented filamentous bacteria (SFB) induce distinct IL-17A negative CD4+ T cell populations in the intestine. We identified furthermore that SFB-induced IL-17-producing CD4+ T cells comprise a heterogenous population including cell subsets being able to produce IL-22. This demonstrates the existence of multiple microbiota-induced CD4+ T cell populations with the capacity to produce IL-22 that develop independently from each other.
As for IL-22BP, we found that IL-22BP producing cells are much more heterogenous than previously anticipated. We are therefore using conditional IL-22BP knock out mouse models to decipher the role of each IL-22BP producing immune cell subset in steady state, IBD, CRC and metastasis. In addition, we have started to analyze the origin of IL-22BP producing T cells. Our results point towards Th1 cells as one origin of IL-22BP producing T cells, but further studies are needed to verify these findings.
As for the role of the intestinal microbiota in regulating IL-22BP we identified that colonization with commensal protozoa induces the expression of IL-22BP in innate immune cells, predominantly DCs and monocyte. Experiments with Il22bp-deficient mice revealed that the IL-22/IL-22BP axis contributes to specific aspects of small intestinal remodeling, e.g. induction of goblet cells and recruitment of innate immune cells, after colonization with non-pathogenic protozoa.
Finally, we have started to extend our studies beyond the IL-22 and IL-22BP axis. We found that faecal microbiota transplantation, short-term dietary manipulation of tryptophan and oral 3-IAA administration increase the efficacy of chemotherapy in humanized gnotobiotic mouse models of pancreatic ductal adenocarcinoma (PDAC). Thus, we identify a microbiota-derived metabolite that has clinical implications in the treatment of PDAC.
Finally, we are spearheading the analysis of IL-22BP producing cells. We found that IL-22BP producing cells are much more heterogenous the previously anticipated and we are currently deciphering the transcriptional network controlling IL-22BP expression as well as the function of these cells in IBD, CRC and metastasis. Furthermore, we will explore how to utilize the specific IL-22/IL-22BP inducing capacities of distinct microbes to counterbalance protective and inflammatory pathways during inflammatory processes. We expect that we are able to have a comprehensive understand of the molecular and functional heterogeneity of IL-22BP producing cells by the end of this project.