Infection by the parasitic helminth Trichinella spiralis activates a Tas2r-mediated signaling pathway in intestinal tuft cells
Infection by the parasitic helminth Trichinella spiralis activates a Tas2r-mediated signaling pathway in intestinal tuft cells
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寄生蠕虫旋毛虫感染激活肠道簇细胞中 Tas2r 介导的信号通路
DOI：
10.1073/pnas.1812901116
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发表时间：
2019-03-19
影响因子：
11.1
通讯作者：
Huang, Liquan
中科院分区：
文献类型：
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作者：
Luo, Xiao-Cui;Chen, Zhen-Huang;Huang, Liquan
寄生蠕虫旋毛虫，对动物和人类构成严重的健康风险，可以在世界各地发现。最近的研究结果表明，一种罕见的肠道上皮细胞，簇细胞，可以检测蠕虫，触发2型免疫反应。然而，潜在的分子机制仍有待充分理解。在这里，我们表明，排泄分泌产物（E-S）和提取物的T。旋毛虫可以刺激细胞因子白细胞介素25（IL-25）从小鼠小肠绒毛中的释放，并引起肠类器官中簇细胞的钙反应，这可以被味觉受体抑制剂异硫氰酸烯丙酯阻断。异源表达的小鼠Tas 2 r味觉受体，其表达在簇细胞增生期间增强，可以响应于E-S和提取物以及苦味化合物水杨苷，而水杨苷反过来可以诱导IL-25从簇细胞释放。此外，G蛋白γ 13亚基的消除、G蛋白α 0/1、G β γ亚基和磷脂酶C β 2的抑制剂的应用显著降低了IL-25的释放。最后，发现簇状细胞利用肌醇三磷酸受体2型（Ip（3）r2）来调节胞质钙，从而调节Trpm 5活性，而甜味化合物甜菊苷对Trpm 5的增强作用增强了簇状细胞IL-25的释放和体内增生。在一起，T。螺旋体感染激活肠簇细胞中的信号通路，其类似于味蕾细胞的信号通路，但具有一些关键差异，以启动2型免疫。
The parasitic helminth Trichinella spiralis, which poses a serious health risk to animals and humans, can be found worldwide. Recent findings indicate that a rare type of gut epithelial cell, tuft cells, can detect the helminth, triggering type 2 immune responses. However, the underlying molecular mechanisms remain to be fully understood. Here we show that both excretory-secretory products (E-S) and extract of T. spiralis can stimulate the release of the cytokine interleukin 25 (IL-25) from the mouse small intestinal villi and evoke calcium responses from tuft cells in the intestinal organoids, which can be blocked by a bitter-taste receptor inhibitor, allyl isothiocyanate. Heterologously expressed mouse Tas2r bitter-taste receptors, the expression of which is augmented during tuft-cell hyperplasia, can respond to the E-S and extract as well as to the bitter compound salicin whereas salicin in turn can induce IL-25 release from tuft cells. Furthermore, abolishment of the G-protein gamma 13 subunit, application of the inhibitors for G-protein alpha o/i, G beta gamma subunits, and phospholipase C beta 2 dramatically reduces the IL-25 release. Finally, tuft cells are found to utilize the inositol triphosphate receptor type 2 (Ip(3)r2) to regulate cytosolic calcium and thus Trpm5 activity, while potentiation of Trpm5 by a sweet-tasting compound, stevioside, enhances tuft cell IL-25 release and hyperplasia in vivo. Taken together, T. spiralis infection activates a signaling pathway in intestinal tuft cells similar to that of taste-bud cells, but with some key differences, to initiate type 2 immunity.