The role of innate immunity in chronic intestinal inflammation and fibrosis: towards a cure for Inflammatory Bowel Disease?

The inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), are chronic relapsing and remitting inflammatory disorders of the gastrointestinal tract, presenting mostly in young adults (peak age of onset 15-30 years). The clinical course of IBD is highly heterogeneous and until now unpredictable. Due to recurrent flares, interspaced with periods of remission, cumulative remodeling of the gut wall occurs and this may lead to strictures (in case of fibrosis with narrowing of the lumen) or fistula (in case of penetrating disease) formation, which in turn cause complications of bowel obstruction and/or perforation with abscesses. These complications are a major source of decreased quality of life, and are also associated with loss of study and work capacity. Preliminary data from our research [Lab of Mucosal Immunology at the Translational Research Center for Gastrointestinal Disorders (TARGID, KU Leuven) clearly showed that intestinal tissue remodeling and fibrosis is mediated by myeloid cells with a “pro-fibrotic” phenotype. Accumulation of these pro-fibrotic myeloid cells in the intestinal microenvironment during chronic remitting inflammation is associated with tissue damage and excessive remodeling of the gut wall resulting in fibrosis. The main goal of the current project will be to evaluate the phenotype and function of pro-fibrotic myeloid cells during colitis both in experimental murine models and samples from patients suffering form IBD, and to investigate the molecules and pathways involved in their generation. Identification of new molecules and pathways involved in the differentiation and accumulation of myeloid cells with a pro-fibrotic phenotype during intestinal inflammation will represent a major breakthrough in elucidating the pathogenesis of IBD and will potentially give rise to a new class of targets to treat and/or prevent fibrosis in patients affected with IBD.