Monocyte-derived macrophages as crucial players in the resolution of inflammation and tissue repair in Inflammatory Bowel Disease

Background. Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract leading to debilitating symptoms. No resolutive therapies are available for IBD, resulting into an invaluable impact on the emotional, financial and social state of the patients and their families. Although over the last few decades most of the studies on IBD have looked into abnormal adaptive immunity, the focus has recently shifted towards alterations of innate immune response. Recent data suggests a causal link between defects in the resolution of inflammation associated with impaired bacterial clearance, excessive cytokines secretion and altered monocyte-macrophage (Mφ) transition in patients with IBD.Study Aims. Our preliminary data indicates that resolution of inflammation during colitis is dependent upon a specific subpopulation of monocyte-derived macrophages with a pro-resolving phenotype. Therefore, the main goal of our project is to clarify the functions of these pro-resolving macrophages during intestinal inflammation, and to investigate the differentiation pathways favoring their pro-resolving phenotype. Unraveling macrophage polarization mechanisms during colitis will elucidate the pathways of inflammation resolution representing a major breakthrough in the pathogenesis of IBD and will be of crucial importance to develop novel therapeutic strategies in our fight against IBD.

Study Design. In the first phase of our project, we will investigate the timing and the phenotypical changes occurring during monocyte differentiation in colitis using in vivo Mφ-specific genetic tracing and loss-of-function studies in pro-resolving Mφs. In the second phase, we aim to translate our findings to the clinical setting by studying the possible contribution of pro-resolving Mφs in the pathogenesis of IBD. To this end, the phenotype and pro-resolving properties of intestinal Mφs will be studied in IBD patients during acute disease and in remission compared to healthy controls.