The TRPA1 ion channel is expressed in CD4+ T cells and restrains T-cell-mediated colitis through inhibition of TRPV1.
The TRPA1 ion channel is expressed in CD4+ T cells and restrains T-cell-mediated colitis through inhibition of TRPV1.
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DOI：
10.1136/gutjnl-2015-310710
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发表时间：
2017-09
期刊：
影响因子：
24.5
通讯作者：
Raz E
中科院分区：
文献类型：
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作者：
Bertin S;Aoki-Nonaka Y;Lee J;de Jong PR;Kim P;Han T;Yu T;To K;Takahashi N;Boland BS;Chang JT;Ho SB;Herdman S;Corr M;Franco A;Sharma S;Dong H;Akopian AN;Raz E
瞬时受体电位锚蛋白-1 （TRPA1）和香草素-1 （TRPV1）是钙（Ca2+）渗透性离子通道，在感觉神经元中主要被称为疼痛受体。然而，越来越多的证据表明它们在IBD的发病机制中起着至关重要的作用。我们探讨了TRPA1和TRPV1在T细胞介导的结肠炎中的可能作用。我们评估了Trpa1基因缺失在两种实验性结肠炎模型（即白细胞介素-10敲除和T细胞过继转移模型）中的作用。我们进行了电生理和Ca2+成像研究来分析TRPA1和TRPV1在CD4+ T细胞中的功能。我们使用遗传和药理学方法来评估TRPV1对Trpa1−/−CD4+ T细胞表型的贡献。我们还分析了IBD患者结肠活检中TRPA1和TRPV1基因表达以及TRPA1+TRPV1+ T细胞浸润情况。我们确定了TRPA1在T细胞介导的结肠炎中的保护作用。我们证实了TRPA1在CD4+ T细胞质膜上的功能性表达，并发现TRPA1−/−CD4+ T细胞增加了T细胞受体（TCR）诱导的Ca2+内流、激活谱和向th1效应细胞的分化。在小鼠和人CD4+ T细胞中，通过基因缺失或药物抑制TRPV1通道，这种表型被消除。最后，我们发现了IBD患者结肠中TRPA1和TRPV1基因表达的差异调控以及TRPA1+TRPV1+ T细胞浸润的增加。我们的研究表明，TRPA1抑制了CD4+ T细胞中TRPV1通道的活性，从而抑制了CD4+ T细胞的活化和结肠炎反应。因此，这些发现可能对人类IBD具有治疗意义。
Transient Receptor Potential Ankyrin-1 (TRPA1) and Vanilloid-1 (TRPV1) are calcium (Ca2+)-permeable ion channels mostly known as pain receptors in sensory neurons. However, growing evidence suggests their crucial involvement in the pathogenesis of IBD. We explored the possible contribution of TRPA1 and TRPV1 to T cell-mediated colitis. We evaluated the role of Trpa1 gene deletion in two models of experimental colitis (i.e., interleukin-10 knockout and T cell adoptive transfer models). We performed electrophysiological and Ca2+ imaging studies to analyze TRPA1 and TRPV1 functions in CD4+ T cells. We used genetic and pharmacological approaches to evaluate TRPV1 contribution to the phenotype of Trpa1−/− CD4+ T cells. We also analyzed TRPA1 and TRPV1 gene expression and TRPA1+TRPV1+ T cell infiltration in colonic biopsies from IBD patients. We identified a protective role for TRPA1 in T cell-mediated colitis. We demonstrated the functional expression of TRPA1 on the plasma membrane of CD4+ T cells and identified that Trpa1−/− CD4+ T cells have increased T-cell receptor (TCR)-induced Ca2+ influx, activation profile and differentiation into Th1-effector cells. This phenotype was abrogated upon genetic deletion or pharmacological inhibition of the TRPV1 channel in mouse and human CD4+ T cells. Finally, we found differential regulation of TRPA1 and TRPV1 gene expression as well as increased infiltration of TRPA1+TRPV1+ T cells in the colon of IBD patients. Our study indicates that TRPA1 inhibits TRPV1 channel activity in CD4+ T cells, and consequently restrains CD4+ T cell activation and colitogenic responses. These findings may therefore have therapeutic implications for human IBD.
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影响因子：
30.5
作者：
Bertin S;Aoki-Nonaka Y;de Jong PR;Nohara LL;Xu H;Stanwood SR;Srikanth S;Lee J;To K;Abramson L;Yu T;Han T;Touma R;Li X;González-Navajas JM;Herdman S;Corr M;Fu G;Dong H;Gwack Y;Franco A;Jefferies WA;Raz E
通讯作者：
Raz E
影响因子：
4.4
作者：
POWRIE, F;LEACH, MW;COFFMAN, RL
通讯作者：
COFFMAN, RL
影响因子：
29.7
作者：
Kaser A;Zeissig S;Blumberg RS
通讯作者：
Blumberg RS
影响因子：
30.5
作者：
Gerlach, Katharina;Hwang, YouYi;Neurath, Markus F.
通讯作者：
Neurath, Markus F.
影响因子：
8
作者：
通讯作者：
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