Intestinal homeostasis depends on tightly regulated interactions between the gut microbiota and the immune system of the host. The epithelial cells are located at the interface between the external environment and the host. Their responses need to be finely regulated in order to enable the onset of protective immunity while preventing aberrant immune responses at the basis of immune disorders such as inflammatory bowel disease (IBD).The mechanisms regulating the epithelial compartment remain poorly understood. During the study, Thomas Marichal and colleagues identified RabGEF1 protein, a guanine nucleotide exchange factor for the endosomal protein Rab5, as a key player of the regulation of epithelial responses. Conditional deletion of RabGEF1 in mouse intestinal epithelial cells is associated with an increased susceptibility to develop a colon pathology similar to IBD. RabGEF1-deficient epithelial cells show impaired endocytosis, an increased activation of the MAP kinase p38 innate signaling pathway, as well as a higher expression of cytokines and chemokines, compared to RabGEF1 expressing cells. In vivo, the developing mouse colon pathology depended of MYD88 as well as of the microbiota. The results in mice suggest that RABGEF1-dependent pathways represent interesting therapeutic targets for the treatment of human IBD..
Reference : El Abbas, S., Radermecker, C., Bai, Q., Beguin, C., Schyns, J., Meunier, M., Pirottin, D., Desmet, C.J., Meuwis, M.A., Art , T., Louis, E., Tam, S.Y., Tsai, M., Bureau, F., Galli, S.J., Marichal, T. (2019). Epithelial RABGEF1 deficiency promotes intestinal inflammation by dysregulating intrinsic MYD88-dependent innate signaling. Mucosal Immunology. https://doi.org/10.1038/s41385-019-0211-z