Dataset Information

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

ABSTRACT: 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.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. (HEPATOLOGY 2013).

SUBMITTER: Deng ZB

PROVIDER: S-EPMC4414328 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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.

Deng Zhong-Bin ZB Zhuang Xiaoying X Ju Songwen S Xiang Xiaoyu X Mu Jingyao J Wang Qilong Q Jiang Hong H Zhang Lifeng L Kronenberg Mitchell M Yan Jun J Miller Donald D Zhang Huang-Ge HG

Hepatology (Baltimore, Md.) 20130211 3

<h4>Unlabelled</h4>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 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/β-catenin pathway activation, including exogenous NKT cell activator, glycolipid α-GalCer, and endogenous prostaglandin E2 ( ...[more]

PMID: 22991247

Similar Datasets

Project description:Natural killer T (NKT) cells are prominent innate-like lymphocytes in the liver with critical roles in immune responses during infection, cancer, and autoimmunity. Interferon gamma (IFN-?) and IL-4 are key cytokines rapidly produced by NKT cells upon recognition of glycolipid antigens presented by antigen-presenting cells (APCs). It has previously been reported that the transcriptional coactivator ?-catenin regulates NKT cell differentiation and functionally biases NKT cell responses toward IL-4, at the expense of IFN-? production. ?-Catenin is not only a central effector of Wnt signaling but also contributes to other signaling networks. It is currently unknown whether Wnt ligands regulate NKT cell functions. We thus investigated how Wnt ligands and ?-catenin activity shape liver NKT cell functions in vivo in response to the glycolipid antigen, ?-galactosylceramide (?-GalCer) using a mouse model. Pharmacologic targeting of ?-catenin activity with ICG001, as well as myeloid-specific genetic ablation of Wntless (Wls), to specifically target Wnt protein release by APCs, enhanced early IFN-? responses. By contrast, within several hours of ?-GalCer challenge, myeloid-specific Wls deficiency, as well as pharmacologic targeting of Wnt release using the small molecule inhibitor IWP-2 impaired ?-GalCer-induced IFN-? responses, independent of ?-catenin activity. These data suggest that myeloid cell-derived Wnt ligands drive early Wnt/?-catenin signaling that curbs IFN-? responses, but that, subsequently, Wnt ligands sustain IFN-? expression independent of ?-catenin activity. Our analyses in ICG001-treated mice confirmed a role for ?-catenin activity in driving early IL-4 responses by liver NKT cells. However, neither pharmacologic nor genetic perturbation of Wnt production affected the IL-4 response, suggesting that IL-4 production by NKT cells in response to ?-GalCer is not driven by released Wnt ligands. Collectively, these data reveal complex temporal roles of Wnt ligands and ?-catenin signaling in the regulation of liver NKT cell activation, and highlight Wnt-dependent and -independent contributions of ?-catenin to NKT cell functions.

Dataset Information

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

Publications

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.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets