Intestinal epithelial cells-derived exosomes provide a bridge between the gut and the liver that prevents liver inflammation through prostaglandin E2 induction of NK T cell anergy (49.11)

Abstract

Abstract The in vivo regulation/induction of NTK anergy has been associated with inhibition of autoimmune and anti-tumor response, but the underlying mechanisms are poorly understood. In this study, we demonstrated that exosomes released from intestinal epithelial cells migrated into liver and induced liver NKT anergy. Unexpectedly, these effects were mediated by an exosomal PGE2 , which were demonstrated in a NKT-mediated liver injury model induced by ConA. Consistent with these findings, blocking PGE2 synthesis attenuated intestinal epithelial cells exosomes mediated inhibition of induction of IFN-γ and IL-4 of α-GalCer stimulated liver NKT cells as a PGE2 receptors mediated and PKA dependent manner. Pro-inflammation condition increased permeability of intestine and thus enhanced accumulation of intestinal epithelial cells exosomes migrated into liver where PGE2 induced NKT anergy in response to subsequently α-GalCer stimulation. Thus, these findings demonstrate a previously unappreciated role for intestinal epithelial cell exosomes served as immune modulator between liver and intestine and maintaining liver NKT homeostasis. Our findings have also important implications for the development of NKT cell-based vaccines and immunotherapies.