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产生乙酰胆碱的 T 细胞增强了固有免疫驱动的结肠炎,但在 T 细胞驱动的结肠炎中是多余的。

Acetylcholine-producing T cells augment innate immune-driven colitis but are redundant in T cell-driven colitis.

机构信息

Amsterdam University Medical Center, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Meibergdreef, Amsterdam, The Netherlands.

Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands.

出版信息

Am J Physiol Gastrointest Liver Physiol. 2019 Nov 1;317(5):G557-G568. doi: 10.1152/ajpgi.00067.2019. Epub 2019 Jul 19.

Abstract

Clinical trials suggest that vagus nerve stimulation presents an alternative approach to classical immune suppression in Crohn's disease. T cells capable of producing acetylcholine (ChAT T cells) in the spleen are essential mediators of the anti-inflammatory effect of vagus nerve stimulation. Besides the spleen, ChAT T cells are found abundantly in Peyer's patches of the small intestine. However, the role of ChAT T cells in colitis pathogenesis is unknown. Here, we made use of CD4ChAT mice (CD4ChAT mice) lacking ChAT expression specifically in CD4 T cells. Littermates (ChAT mice) served as controls. In acute dextran sulfate sodium (DSS)-induced colitis (7 days of 2% DSS in drinking water), CD4ChAT mice showed attenuated colitis and lower intestinal inflammatory cytokine levels compared with ChAT mice. In contrast, in a resolution model of DSS-induced colitis (5 days of 2% DSS followed by 7 days without DSS), CD4ChAT mice demonstrated a worsened colitis recovery and augmented colonic histological inflammation scores and inflammatory cytokine levels as compared with ChAT mice. In a transfer colitis model using CD4CD45RB T cells, T cells from CD4ChAT mice induced a similar level of colitis compared with ChAT T cells. Together, our results indicate that ChAT T cells aggravate the acute innate immune response upon mucosal barrier disruption in an acute DSS-induced colitis model, whereas they are supporting the later resolution process of this innate immune-driven colitis. Surprisingly, ChAT expression in T cells seems redundant in the context of T cell-driven colitis. By using different mouse models of experimental colitis, we provide evidence that in dextran sulfate sodium-induced colitis, ChAT T cells capable of producing acetylcholine worsen the acute immune response, whereas they support the later healing phase of this innate immune-driven colitis.

摘要

临床试验表明,迷走神经刺激为克罗恩病的经典免疫抑制提供了一种替代方法。脾脏中能够产生乙酰胆碱的 T 细胞(ChAT T 细胞)是迷走神经刺激抗炎作用的重要介质。除了脾脏,ChAT T 细胞在小肠的派尔集合淋巴结中大量存在。然而,ChAT T 细胞在结肠炎发病机制中的作用尚不清楚。在这里,我们利用缺乏 CD4 T 细胞中 ChAT 表达的 CD4ChAT 小鼠(CD4ChAT 小鼠)。同窝小鼠(ChAT 小鼠)作为对照。在急性葡聚糖硫酸钠(DSS)诱导的结肠炎(饮用水中 2% DSS 持续 7 天)中,与 ChAT 小鼠相比,CD4ChAT 小鼠的结肠炎明显减轻,肠道炎症细胞因子水平降低。相比之下,在 DSS 诱导的结肠炎缓解模型(2% DSS 持续 5 天,然后无 DSS 持续 7 天)中,与 ChAT 小鼠相比,CD4ChAT 小鼠的结肠炎恢复更差,结肠组织学炎症评分和炎症细胞因子水平升高。在使用 CD4CD45RB T 细胞的转移结肠炎模型中,与 ChAT T 细胞相比,来自 CD4ChAT 小鼠的 T 细胞诱导了类似水平的结肠炎。总之,我们的结果表明,在急性 DSS 诱导的结肠炎模型中,ChAT T 细胞在黏膜屏障破坏时加剧急性先天免疫反应,而在这种先天免疫驱动的结肠炎的后期缓解过程中,ChAT T 细胞则起到支持作用。令人惊讶的是,在 T 细胞驱动的结肠炎中,T 细胞中的 ChAT 表达似乎是多余的。通过使用不同的实验性结肠炎小鼠模型,我们提供的证据表明,在葡聚糖硫酸钠诱导的结肠炎中,能够产生乙酰胆碱的 ChAT T 细胞会加重急性免疫反应,而在这种先天免疫驱动的结肠炎的后期愈合阶段,ChAT T 细胞则会起到支持作用。

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