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.
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.
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DOI：
10.1002/hep.26086
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发表时间：
2013-03
期刊：
影响因子：
13.5
通讯作者：
Zhang, Huang-Ge
中科院分区：
文献类型：
--
作者：
Deng, Zhong-Bin;Zhuang, Xiaoying;Ju, Songwen;Xiang, Xiaoyu;Mu, Jingyao;Wang, Qilong;Jiang, Hong;Zhang, Lifeng;Kronenberg, Mitchell;Yan, Jun;Miller, Donald;Zhang, Huang-Ge
已知Wnt/β-catenin通路在诱导免疫耐受中起作用，但其在诱导和维持NKT细胞能量中的作用尚不清楚。我们发现肝脏微环境中Wnt通路的激活对于诱导NKT细胞能量是重要的。我们发现了许多触发Wnt/β-catenin通路激活的刺激，包括外源性NKT细胞激活剂、糖脂α-GalCer和内源性PGE2。糖脂α-GalCer处理小鼠可诱导肝脏中wnt3a和wnt5a的表达，随后导致肝脏微环境诱导NKT细胞能量向α-GalCer再刺激。我们还发现纳米颗粒携带的循环PGE2是稳定的，并且这些纳米颗粒是A33+。A33+是肠上皮细胞的标记物，这表明纳米颗粒来源于肠道。PGE2与肠黏液衍生外泌体样纳米颗粒（IDEN）相关处理小鼠可诱导NKT细胞能量。PGE2处理导致NKT细胞GSK-3β失活，从而激活Wnt/β-catenin通路。在糖脂递呈和tlr介导的途径中，idin相关的PGE2还通过改变dc诱导IL-12和IFN-β的能力来诱导NKT细胞的能量。这些发现表明，IDEN相关的PGE2作为肝脏和肠道之间的内源性免疫调节剂，维持肝脏NKT细胞的稳态，这一发现对基于NKT细胞的免疫疗法的发展具有重要意义。
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.
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影响因子：
64.5
作者：
Goessling W;North TE;Loewer S;Lord AM;Lee S;Stoick-Cooper CL;Weidinger G;Puder M;Daley GQ;Moon RT;Zon LI
通讯作者：
Zon LI
影响因子：
15.9
作者：
Halder, Ramesh C.;Aguilera, Carlos;Kumar, Vipin
通讯作者：
Kumar, Vipin
影响因子：
30.5
作者：
Ioannidis, V;Beermann, F;Held, W
通讯作者：
Held, W
DOI：
10.1016/s1521-6934(03)00043-9
发表时间：
2003-10-01
影响因子：
5.5
作者：
Bygdeman, M
通讯作者：
Bygdeman, M
DOI：
10.4049/jimmunol.0901208
发表时间：
2010-02-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Lombardi V;Stock P;Singh AK;Kerzerho J;Yang W;Sullivan BA;Li X;Shiratsuchi T;Hnatiuk NE;Howell AR;Yu KO;Porcelli SA;Tsuji M;Kronenberg M;Wilson SB;Akbari O
通讯作者：
Akbari O