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

Abstract

The Wnt/β-catenin pathway has been known to play a role in induction of immune tolerance, but its role in the induction and maintenance of NKT cell anergy is unknown. We found that activation of the Wnt pathway(s) in the liver microenvironment is important for induction of NKT cell anergy. We identified a number of stimuli triggering Wnt/β-catenin pathway activation, including exogenous NKT cell activator, glycolipid α-GalCer, and endogenous PGE2. Glycolipid α-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 α-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 (IDEN) induced NKT cell anergy. PGE2 treatment leads to activation of the Wnt/β-catenin pathway by inactivation of GSK-3β of NKT cells. IDEN-associated PGE2 also induces NKT cell anergy through modification of the ability of DCs to induce IL-12 and IFN-β in the context of both glycolipid presentation and TLR-mediated pathways. These findings demonstrate that IDEN associated PGE2 serves as an endogenous immune modulator between the liver and intestines and maintains liver NKT cell homeostasis and this finding has implications for development of NKT cell–based immunotherapies.

Hepatic sinusoids in liver injury, inflammation, and fibrosis: new pathophysiological insights

“…In the liver, those are liver epithelia (hepatocytes, cholangiocytes), natural killer T cells, HSC, and SEC [68]. Of interest, liver cells have been shown to be targets even for exosomes originating from other organs such as the intestine [74]. The current knowledge about the role of exosomes in liver diseases has been discussed previously by Masyuk et al [68], who reviewed the involvement of exosomes in HCC, HCV, and liver inflammation, and their potential role as early diagnostic and prognostic markers from the urine or blood.…”

Exosomes in the pathogenesis, diagnostics and therapeutics of liver diseases

“…Both types of liver epithelia (i.e., hepatocytes and cholangiocytes), natural killer T (NKT) cells, hepatic stellate cells, adult liver stem cells, and hepatic sinusoidal endothelial cells are exosome-releasing and/or exosome-targeting cells [6,8–12]. Hepatocyte- and cholangiocyte-derived exosomes are involved in hepatocyte-to-cholangiocyte, cholangiocyte-to-cholangiocyte and cholangiocyte-to-hepatic sinusoidal endothelial cell communication [6,10].…”

“…For example, exosomes derived from the intestinal epithelial cells carry prostaglandin E2 and induce liver immune tolerance by communicating directly with the liver NTK cells via the Wnt/β-catenin signaling pathway [8]. …”

Exosome-like Nanoparticles from Intestinal Mucosal Cells Carry Prostaglandin E2 and Suppress Activation of Liver NKT Cells

“…We also demonstrate that IDENs can induce an anergic-like state in liver NKT cells. Induction of a NKT cell anergic-like state by IDENs occurs through a previously undescribed mechanism where the transport of prostaglandin E 2 (PGE 2 ) by the IDENs(16) into the liver creates an environment that promotes the NKT cell anergic-like state.…”