Immune-stromal crosstalk in inflammation and fibrosis: Exploiting the spatiotemporal dynamics of the OSM-OSMR axis in inflammatory bowel disease to develop novel antifibrotic therapies

Intestinal fibrosis is a common and serious complication of inflammatory bowel disease (IBD). While intestinal inflammation can be treated pharmacologically based on our current 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 crucial component of IBD pathogenesis. Our research discovered that the IL-6 family cytokine oncostatin-M (OSM) plays a central role in immune-stromal crosstalk in human IBD, and drives pro-inflammatory responses in patients with refractory disease. Genetic deletion of OSM significantly reduced acute intestinal inflammation. Furthermore, our current findings suggest that OSM is required for intestinal remodeling and the regulation of collagen homeostasis by controlling immune cell recruitment. Thus, the OSM-OSMR axis serves as a rheostat for tissue inflammation and repair. We will investigate how OSM modulates intestinal fibrosis and identify upstream and downstream signaling events controlling intestinal fibrosis. 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 stromal cells driving intestinal fibrosis. This project will deepen our understanding of the intestinal aberrant tissue repair mechanisms acting in IBD and other fibrotic diseases, define novel biomarkers to identify patients at risk of fibrosis and provide the means to prevent and treat fibrotic disease.