title: 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 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 (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 (IDENs) induced NKT cell anergy. PGE2 treatment leads to activation of the Wnt/β-catenin pathway by inactivation of glycogen synthase kinase 3β 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-β in the context of both glycolipid presentation and Toll-like receptor-mediated pathways.
  
  
  CONCLUSIONS
  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).
authors.affiliation: Louisville Veterans Administration Medical Center, Department of Microbiology & Immunology, Brown Cancer Center, University of Louisville, KY 40202, USA. z0deng01@louisville.edu
authors.forename: Zhong-Bin
authors.initials: ZB
authors.lastname: Deng
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zhuang
authors.forename: Songwen
authors.initials: S
authors.lastname: Ju
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Xiang
authors.forename: Jingyao
authors.initials: J
authors.lastname: Mu
authors.forename: Qilong
authors.initials: Q
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.forename: Lifeng
authors.initials: L
authors.lastname: Zhang
authors.forename: Mitchell
authors.initials: M
authors.lastname: Kronenberg
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.forename: Donald
authors.initials: D
authors.lastname: Miller
authors.forename: Huang-Ge
authors.initials: HG
authors.lastname: Zhang
mesh_terms: D000818:Animals; D060833:Cellular Microenvironment / Q000276:immunology; D017635:Clonal Anergy / Q000187:drug effects / Q000276:immunology; D015232:Dinoprostone / Q000276:immunology / Q000378:metabolism; D005699:Galactosylceramides / Q000494:pharmacology; D007108:Immune Tolerance / Q000276:immunology; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008099:Liver / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009093:Mucus / Q000276:immunology / Q000378:metabolism; D053758:Nanoparticles; D051153:Wnt Proteins / Q000276:immunology / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000276:immunology; D000071818:Wnt-5a Protein; D060509:Wnt3A Protein / Q000276:immunology / Q000378:metabolism*; D051176:beta Catenin / Q000276:immunology / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; D005699:Galactosylceramides; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; C438615:Wnt5a protein, mouse; C493154:alpha-galactosylceramide; D051176:beta Catenin; D015232:Dinoprostone