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