Intestinal mucus-derived nanoparticle-mediated activation of Wnt/??-catenin signaling plays a role in induction of liver natural killer T cell anergy in mice

摘要

The Wnt/??-catenin pathway has been known to play a role in induction of immune tolerance, but its role in the induction and maintenance of natural killer T (NKT) cell anergy is unknown. We found that activation of the Wnt pathways in the liver microenvironment is important for induction of NKT cell anergy. We identified a number of stimuli triggering Wnt/??-catenin pathway activation, including exogenous NKT cell activator, glycolipid ??-GalCer, and endogenous prostaglandin E2 (PGE2). Glycolipid ??-GalCer treatment of mice induced the expression of wnt3a and wnt5a in the liver and subsequently resulted in a liver microenvironment that induced NKT cell anergy to ??-GalCer restimulation. We also found that circulating PGE2 carried by nanoparticles is stable, and that these nanoparticles are A33+. A33+ is a marker of intestinal epithelial cells, which suggests that the nanoparticles are derived from the intestine. Mice treated with PGE2 associated with intestinal mucus-derived exosome-like nanoparticles (IDENs) induced NKT cell anergy. PGE2 treatment leads to activation of the Wnt/??-catenin pathway by inactivation of glycogen synthase kinase 3?? of NKT cells. IDEN-associated PGE2 also induces NKT cell anergy through modification of the ability of dendritic cells to induce interleukin-12 and interferon-?? in the context of both glycolipid presentation and Toll-like receptor-mediated pathways. Conclusion: These findings demonstrate that IDEN-associated PGE2 serves as an endogenous immune modulator between the liver and intestines and maintains liver NKT cell homeostasis. This finding has implications for development of NKT cell-based immunotherapies. ? 2012 American Association for the Study of Liver Diseases.