Interplay of epithelial mechanics and neutrophil activation as a pathomechanism in refractory IBD and colorectal cancer patients

Description du projet

Dynamique épithéliale dans les maladies inflammatoires de l’intestin

Les maladies inflammatoires de l’intestin (MII), dont la maladie de Crohn et la colite ulcéreuse, se caractérisent par une inflammation de longue durée de l’appareil digestif. Bien que les traitements neutralisant le facteur de nécrose tumorale, une cytokine pro-inflammatoire, aient amélioré les résultats chez les patients, de nombreuses personnes ne réagissent toujours pas au traitement ou développent une résistance au fil du temps. Avec le soutien du programme Actions Marie Skłodowska-Curie, le projet INTERCONNECTIONS concentre ses recherches sur les changements mécaniques que les cellules épithéliales intestinales peuvent subir et qui déclenchent l’inflammation et la résistance aux thérapies. L’hypothèse de travail est que la dynamique épithéliale influence la façon dont les cellules immunitaires, telles que les neutrophiles, migrent à travers les tissus environnants et les remodèlent. En révélant comment ces processus façonnent la matrice extracellulaire et le comportement des fibroblastes, le projet entend identifier de nouvelles cibles moléculaires pour des traitements plus efficaces des MII.

Objectif

Inflammatory bowel diseases (IBD) are a heterogeneous group of disorders characterized by gastrointestinal tract inflammation, being Crohn's Disease and Ulcerative Colitis, the most clinically abundant. IBD affects around 6.8 million people all over the world, being Europe the continent with the highest prevalence. Although anti-TNF-α monoclonal antibodies are a breakthrough therapy, almost 40% of IBD patients do not respond to therapy or acquire resistance. This leads to uncontrolled inflammation that, prolonged in time, constitutes a higher Colorectal Cancer risk. This justifies the current efforts to identify innovative therapy targets for IBD understanding of the molecular processes behind (personalized medicine). The fact that an increased intestinal permeability precedes the onset of inflammation possesses epithelial disruption as a potential etiological factor in IBD. Moreover, in recent years, several publications have highlighted that an impaired epithelial barrier is linked to resistance to therapy. Nevertheless, how altered epithelial mechanics can influence the structural properties of the extracellular matrix and immune cells migrating through it is not fully understood. On the other hand, the role of neutrophils as resistance-to-therapy players has emerged very recently. Then, we hypothesize that an alteration in epithelial cell mechanics constitutes a primary event that impacts the proliferation and behavior of the first immune cell responders: neutrophils. This would further contribute to ECM remodeling and fibroblasts polarization to IAFs (another mechanism implicated in therapy resistance). Then, INTERCONNECTIONS aims to elucidate how an altered epithelial dynamics constitutes a primary event that directly (through an altered transepithelial migration) or indirectly (affecting the mechanical framework) could promote the accumulation of activated neutrophils.