The liver-brain-gut neural arc maintains the Treg cell niche in the gut
The liver-brain-gut neural arc maintains the Treg cell niche in the gut
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DOI：
10.1038/s41586-020-2425-3
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发表时间：
2020-06-11
期刊：
影响因子：
64.8
通讯作者：
Kanai, Takanori
中科院分区：
文献类型：
--
作者：
Teratani, Toshiaki;Mikami, Yohei;Kanai, Takanori
肝脏-大脑-肠道神经回路对肠道微环境做出反应，并通过控制肠道抗原呈递细胞以毒鼠碱依赖的方式调节结肠中外周调节性T细胞的活动。最近的临床和实验证据唤起了肠道-脑轴的概念，以解释中枢神经系统和肠道微生物区系之间的相互作用，这些相互作用与炎症性肠病和中枢神经系统疾病的双向效应密切相关(1-4)。尽管我们对神经免疫相互作用的了解最近取得了进展，但仍不清楚肠道和大脑如何沟通以维持肠道免疫稳态，包括诱导和维持外周调节性T细胞(PT(Reg)细胞)，以及什么环境信号促使宿主保护自己免受炎症性肠病的发展。在这里，我们报告了一个肝-脑-肠道神经弧，它确保肠道中PT(Reg)细胞的正确分化和维持。肝脏迷走神经感觉传入神经负责间接感觉肠道微环境，并将感觉传入传递到脑干孤束核，最终传递到迷走神经和肠神经元。外科手术和化学干扰肝脏传入水平的迷走神经感觉传入减少了结肠PT(Reg)细胞的丰度；这归因于乙醛脱氢酶(ALDH)的表达和肠道抗原提呈细胞合成视黄酸的减少。乙酰胆碱受体的激活直接诱导了人和小鼠结肠抗原提呈细胞中ALDH基因的表达，而这些受体的遗传消融在体外取消了对抗原提呈细胞的刺激。在结肠炎小鼠模型中，从肝脏到脑干的左侧迷走神经感觉传入中断，减少了结肠PT(Reg)细胞池，导致结肠炎易感性增加。这些结果表明，新的迷走神经-迷走神经-肝脏-脑-肠道反射弧控制着PT(Reg)细胞的数量，并维持肠道内环境的稳定。对这种自主反馈前馈系统的干预可以帮助制定治疗策略，以治疗或预防肠道免疫疾病。
A liver-brain-gut neural circuit responds to the gut microenvironment and regulates the activity of peripheral regulatory T cells in the colon by controlling intestinal antigen-presenting cells in a muscarinic signalling-dependent manner.Recent clinical and experimental evidence has evoked the concept of the gut-brain axis to explain mutual interactions between the central nervous system and gut microbiota that are closely associated with the bidirectional effects of inflammatory bowel disease and central nervous system disorders(1-4). Despite recent advances in our understanding of neuroimmune interactions, it remains unclear how the gut and brain communicate to maintain gut immune homeostasis, including in the induction and maintenance of peripheral regulatory T cells (pT(reg)cells), and what environmental cues prompt the host to protect itself from development of inflammatory bowel diseases. Here we report a liver-brain-gut neural arc that ensures the proper differentiation and maintenance of pT(reg)cells in the gut. The hepatic vagal sensory afferent nerves are responsible for indirectly sensing the gut microenvironment and relaying the sensory inputs to the nucleus tractus solitarius of the brainstem, and ultimately to the vagal parasympathetic nerves and enteric neurons. Surgical and chemical perturbation of the vagal sensory afferents at the hepatic afferent level reduced the abundance of colonic pT(reg)cells; this was attributed to decreased aldehyde dehydrogenase (ALDH) expression and retinoic acid synthesis by intestinal antigen-presenting cells. Activation of muscarinic acetylcholine receptors directly inducedALDHgene expression in both human and mouse colonic antigen-presenting cells, whereas genetic ablation of these receptors abolished the stimulation of antigen-presenting cells in vitro. Disruption of left vagal sensory afferents from the liver to the brainstem in mouse models of colitis reduced the colonic pT(reg)cell pool, resulting in increased susceptibility to colitis. These results demonstrate that the novel vago-vagal liver-brain-gut reflex arc controls the number of pT(reg)cells and maintains gut homeostasis. Intervention in this autonomic feedback feedforward system could help in the development of therapeutic strategies to treat or prevent immunological disorders of the gut.