Intestinal fibrosis is a common and severe complication of inflammatory bowel disease (IBD). While intestinal inflammation can be treated pharmacologically based on our recent understanding of the underlying pathogenesis, little is known about the mechanisms driving fibrogenesis. Thus, no approved therapies exist for intestinal fibrosis. While stromal cells lie at the heart of fibrogenesis, our knowledge of how immune-derived signals instruct aberrant tissue repair and fibrosis is limited. We recently highlighted that the immune-stromal cell axis is a critical component of IBD pathogenesis. Our research identified the IL-6 family cytokine oncostatin-M (OSM) as a central mediator of immune-stromal crosstalk in human IBD and a driver of pro-inflammatory responses in patients with treatment-refractory disease. Genetic deletion or pharmacological blockade of OSM significantly reduced acute intestinal inflammation. Furthermore, our current findings support that OSM is required for intestinal remodeling and regulation of collagen homeostasis. Therefore, the OSM-OSMR axis is a prototypic example of immune-stromal crosstalk in the intestinal mucosa. Exploring the OSM-OSMR axis provides a unique opportunity to study the dialogue between stromal and immune cells in inflammation and aberrant tissue repair. As a physician-scientist, I will use (i) newly generated reporter and conditional knock-out mice, (ii) contemporary mouse models of intestinal inflammation and fibrosis, (iii) primary human tissue samples from carefully clinically annotated IBD patients with intestinal fibrosis, and (iv) cutting-edge technologies including single-cell sequencing and imaging mass cytometry to dissect the crosstalk between the immune system and mesenchymal cells driving intestinal fibrosis, with a particular focus on the OSM-OSMR axis. This project will deepen our understanding of the intestinal fibrotic niche and aberrant tissue repair mechanisms acting in IBD and other fibrotic diseases, define novel biomarkers to identify patients at risk of fibrosis, and identify new approaches to prevent and treat fibrotic disease.
Initiative: Lichtenberg - Professuren
Funding period: 05.2018 - 04.2026
Microbial and environmental factors that control gut-resident memory T cells in human health and disease: molecular signatures, function, and interaction partners
The human intestine harbours a vast and diverse bacterial community that exerts several beneficial effects on the host such as a profound effect on immune responses. Maladaptation of this host-microbe dialogue can promote inflammatory responses and is implicated in various pathologies including inflammatory bowel disease (IBD). However, the microbial signals and molecular pathways that promote tissue-specific differentiation of gut-resident immune cells are still poorly characterized. Using cutting-edge technologies, a multidisciplinary approach, well-defined patient cohorts, and mouse models of colitis, this project aims at deciphering the complex host-microbiota relationship, i.e. the interactions between microbial, environmental, and inflammatory factors that promote intestinal inflammation. The overall goal is to utilize the acquired knowledge to identify targetable cytokine signals and pathogenic molecular pathways in microbiota-specific CD4+ T cell populations for therapeutic development in IBD.
Initiative: SFB/Transregio 241
Founding period: 07.2018-06.2026
A05: Oncostatin M - a novel cytokine in inflammatory bowel diseases pathogenesis
Oncostatin M (OSM) is a highly expressed cytokine in IBD and high pretreatment expression is strongly associated with failure of anti-TNF-a therapy. OSM promotes intestinal inflammatory pathology and genetic deletion or pharmacological blockade of OSM significantly attenuates colitis in mice. Our hypothesis is that OSM acts as an inflammatory amplifier and driver of disease chronicity by impacting on both stromal and epithelial cells. We believe that a better understanding of OSM-OSMR pathway in intestinal biology could facilitate the development of novel therapeutic strategies targeting this pathway in IBD.
