Deciphering the role of stromal IL36R signalling for the resolution of intestinal inflammation and fibrosis

• Applicants: Dr. Kristina Koop; Professor Clemens Neufert, Ph.D.
• Subject Area: Gastroenterology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 539236816

Failure to resolve intestinal inflammation is a key feature of patients with inflammatory bowel disease (IBD) and can promote long-term complications such as fibrotic strictures requiring surgery. Published own work has shown that Interleukin 36 receptor (IL36R) signalling plays an important role in the maintenance of intestinal inflammation and fibrosis. While the IL36R is expressed by a variety of cell types, there is increasing evidence that intestinal stromal cells, e.g. inflammatory fibroblasts, play a critical role in IBD and orchestrate the perpetuation of intestinal inflammation with lack of resolution, e.g. in situations where the process becomes resistant to inhibition of tumor necrosis factor (TNF) alpha. In the proposed project, we hypothesise that IL36-mediated activation of intestinal stromal cells is a key process in preventing resolution of inflammation and inducing chronic fibrotic tissue responses in the gut. Therefore, we aim to investigate the role of fibroblast-specific IL36R signalling in the resolution of intestinal inflammation and fibrosis. We hypothesise that fibroblast-specific inhibition of IL36R activation and modulation of different fibroblast subsets may promote resolution of chronic intestinal inflammation and fibrosis. To address this topic, our work plan is divided into a murine and a human part and includes multidimensional analysis of IBD patient samples and in vivo studies in genetically modified mice. Aim 1 will analyse the influence of fibroblast-specific IL36R signalling on the course of intestinal inflammation and fibrosis in vivo using a novel conditional knockout mouse strain. Aim 2 will include a comprehensive molecular analysis of different fibroblast subsets as target cells of IL36R ligands in human IBD, including patient subgroups such as anti-TNF responders vs. anti-TNF non-responders. Aim 3 will include functional in vitro studies addressing IL36-driven plasticity of different fibroblast subsets and its impact on inflammation and fibrosis. Planned readouts will include molecular imaging technologies such as multiphoton microscopy, imaging CyTOF, lightsheet microscopy and single cell RNA sequencing to comprehensively analyse inflammatory vs. pro-resolving molecular pathways. In summary, this project aims to characterise the contribution of fibroblast-related IL36R signalling to the maintenance of intestinal inflammation and fibrosis and may pave the way for the development of novel therapeutic options that promote resolution of intestinal inflammation and inhibit fibrosis and stricture development in the gut.

• DFG Programme: Research Grants