The role of immune cell migration in gut-liver crosstalk during homeostasis, tolerance, and inflammation

点击翻译按钮获取中文摘要

Directed migration of immune cells is critical for the regulation of immune responses and is secured by the specificity and interactions of chemokines and adhesion molecules. As a therapeutic approach, selective inhibition of immune cell migration has already reached the stage of clinical application. A prerequisite for targeted inhibition is the identification of the disease promoting cell types, their migration behavior, the homing receptors responsible, and the functions of those receptors. In recent years we have dissected the functions of the adhesion molecules beta7 integrin and MAdCAM-1 by generating and analyzing gene-targeted mice. This has demonstrated that beta7 integrin and MAdCAM-1 are essential for the migration of immune cells into the gastrointestinal tract and contribute to immunogenic and tolerogenic immune responses by recruiting the necessary cells. We now wish to extend our studies to the liver. All nutrients absorbed by the intestine pass through the liver, aberrant immune responses in the gut can induce liver pathology, and oral tolerance, a critical mechanism preventing immune reaction towards harmless nutritive antigens, can be induced in the liver. We therefore plan to delineate the contribution of gut-tropic adhesion molecules to homeostatic and inflammatory gut-liver crosstalk. Utilizing adhesion molecule-deficient mice, we will first need to determine how adhesion molecules contribute to liver-specific migration and localization of immune cells in homeostasis. Moreover, the role of immune cell migration under inflammatory conditions will be evaluated in experimental models of hepatitis. By combining experimental IBD and hepatitis models, we then aim to identify migration-dependent consequences of IBD that might support liver inflammation. We also want to define the role of adhesion molecule-dependent cell migration for the plasmacytoid dendritic cell (pDC) mediated induction of oral tolerance. pDCs are critically involved in oral tolerance established in the liver but it is not yet known how pDCs migrate to the liver and whether there is pDC trafficking from the gut to the liver. We plan to address this issue in vivo by a series of pDC transfer experiments in the context of immunization and tolerization.Modulation of immune cell migration for control of chronic inflammation in humans is now recognized as an important therapeutic advance. Thus, by improving our understanding of biologicals that modulate cell migration and helping to shape their future use, our studies will be of great value.