MyD88 and retinoic acid signaling pathways interact to modulate gastrointestinal activities of dendritic cells.
MyD88 and retinoic acid signaling pathways interact to modulate gastrointestinal activities of dendritic cells.
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DOI：
10.1053/j.gastro.2011.04.010
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发表时间：
2011-07
期刊：
影响因子：
29.4
通讯作者：
Mora JR
中科院分区：
文献类型：
--
作者：
Villablanca EJ;Wang S;de Calisto J;Gomes DC;Kane MA;Napoli JL;Blaner WS;Kagechika H;Blomhoff R;Rosemblatt M;Bono MR;von Andrian UH;Mora JR
肠相关树突状细胞（DC）将维生素A代谢成全反式视黄酸（RA），其是诱导淋巴细胞定位于胃肠道（GI）并促进Foxp 3+调节性T细胞（Treg）和免疫球蛋白（IG）A抗体分泌细胞（IgA-ASC）分化所需的。我们研究了RA是否在一个正反馈回路中起作用，通过DC来诱导其自身的合成。我们测量了小鼠肠组织中类维生素A的水平，并评估了RA在细胞培养物和小鼠肠相关DC活动中的作用。我们使用药理学拮抗剂来确定参与DC调节的信号通路，并使用MyD 88 −/−小鼠来确定Toll样受体（TLR）信号在RA介导的DC活动中的作用。类维生素A的浓度沿肠沿着呈近端至远端梯度下降，这与肠特异性DC的活性相关。重要的是，RA调节肠道相关DC产生RA、诱导T细胞定位于胃肠道并产生Treg和伊加分泌细胞的能力。RA是足以诱导其自身生产的肠外DC，在体外和体内。RA介导的DC调节需要通过丝裂原活化蛋白激酶信号通路的信号传导，并且意外地需要MyD 88，其与TLR、白细胞介素（IL）-1和IL-18信号传导相关。RA是诱导DC调节T细胞定位于胃肠道和伊加分泌的必要和充分条件。这些发现表明RA受体和MyD 88依赖性TLR信号通路之间存在串扰。
Gut-associated dendritic cells (DC) metabolize vitamin A into all-trans retinoic acid (RA), which is required to induce lymphocytes to localize to the gastrointestinal (GI) tract and promotes the differentiation of Foxp3+ regulatory T cells (TREG) and immunoglobulin (Ig)A antibody-secreting cells (IgA-ASC). We investigated whether RA functions in a positive-feedback loop, via DC, to induce its own synthesis. We measured levels of retinoids in intestine tissues from mice and assessed the role of RA in activities of gut-associated DC in cell cultures and mice. We used pharmacologic antagonists to determine the signaling pathways involved in regulation of DC and used MyD88−/− mice to determine the contribution of Toll-like receptor (TLR) signaling in RA-mediated activities of DC. The concentration of retinoids decreased in a proximal-to-distal gradient along the intestine, which correlated with the activity of gut-specific DC. Importantly, RA regulated the ability of gut-associated DC to produce RA, induce T cells to localize to the GI tract, and generate TREG and IgA secreting cells. RA was sufficient to induce its own production by extra-intestinal DC, in vitro and in vivo. RA-mediated regulation of DC required signaling through the mitogen-activated protein kinase signaling pathway and unexpectedly required MyD88, which has been associated with TLR, interleukin (IL)-1, and IL-18 signaling. RA is necessary and sufficient to induce DC to regulate T-cell localization to the GI tract and IgA secretion. These findings indicate crosstalk between the RA receptor and MyD88-dependent TLR signaling pathways.
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