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肝脑肠神经弧维持肠道Treg细胞的生态位
2020-06-12 22:03

日本庆应义塾大学医学院Takanori Kanai和Yohei Mikami研究组取得最新进展。他们表明肝脑肠神经弧维持肠道Treg细胞的生态位。该研究于2020年6月11日发表于国际学术期刊《自然》杂志上。

他们报告了一种新型的肝脑肠神经弧,可确保肠道中外周调节性T细胞(pTreg细胞)细胞的适当分化和维持。肝迷走神经感觉传入负责间接感测肠道微环境,并将感觉输入传递至脑干的孤束核,最终到达迷走副交感神经和肠神经元。迷走神经感觉传入神经在肝传入水平的手术和化学扰动严重损害了结肠pTreg细胞,这归因于肠道抗原呈递细胞(APC)的醛脱氢酶(ALDH)表达和视黄酸(RA)合成受损。毒蕈碱Ach受体(mAChR)激活直接诱导人和小鼠结肠APC中的ALDH基因表达,而mAChR的基因缺失消除了APC在体外的兴奋性。

在结肠炎模型中,从肝脏到脑干的左迷走感觉传入的中断减少了结肠pTreg库,导致对结肠炎的敏感性增加。这些结果表明,新颖的迷走神经-肝-脑-胆汁反射弧可以调节pTreg细胞的数量并保持肠道稳态。干预这种自主反馈的前馈系统可以帮助开发新的治疗策略,以治疗或预防肠道免疫系统疾病。

据了解,肠-脑轴是中枢神经系统(CNS)与周围肠道功能之间的双向相互作用,在概念上是可行的最近的临床和实验证据显示,肠疾病(IBDs)和中枢神经系统疾病中,CNS与肠道菌群之间的相互作用与炎症的双向作用密切相关。尽管最近人们对神经免疫相互作用的理解有了新进展,但尚不清楚肠道和大脑如何交流以维持肠道免疫稳态,包括诱导和维持pTreg细胞,以及哪些环境因素促使宿主保护宿主免于IBD。

附:英文原文

Title: The liver–brain–gut neural arc maintains the T reg cell niche in the gut

Author: Toshiaki Teratani, Yohei Mikami, Nobuhiro Nakamoto, Takahiro Suzuki, Yosuke Harada, Koji Okabayashi, Yuya Hagihara, Nobuhito Taniki, Keita Kohno, Shinsuke Sibata, Kentaro Miyamoto, Harumichi Ishigame, Po-Sung Chu, Tomohisa Sujino, Wataru Suda, Masahira Hattori, Minoru Matsui, Takaharu Okada, Hideyuki Okano, Masayuki Inoue, Toshihiko Yada, Yuko Kitagawa, Akihiko Yoshimura, Mamoru Tanida, Makoto Tsuda, Yusaku Iwasaki, Takanori Kanai

Issue&Volume: 2020-06-11

Abstract: The gut–brain axis, a reciprocal interaction between the central nervous system (CNS) and peripheral intestinal functions, is conceptually feasible from recent clinical and experimental evidence showing mutual interactions between the CNS and gut microbiota that are closely associated with the bidirectional effects of inflammatory bowel diseases (IBDs) and CNS disorders1–4. Despite recent advances in our understanding of neuroimmune interactions, it remains unclear how the gut and brain communicate to maintain gut immune homeostasis, including induction and maintenance of peripheral regulatory T cells (pTreg cells) and what environmental cues prompt the host to protect host from development of IBDs. Here, we report a novel liver-brain-gut neural arc that ensures proper differentiation and maintenance of pTreg cells in the gut. The hepatic vagal sensory afferents were 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 significantly impaired colonic pTreg cells, which was attributed to impairment of aldehyde dehydrogenase (ALDH) expression and retinoic acid (RA) synthesis by intestinal antigen-presenting cells (APCs). Muscarinic Ach receptor (mAChR) activation directly induced ALDH gene expression both in human and mouse colonic APCs, whereas genetic ablation of mAChRs abolished APC excitement in vitro. Disruption of left vagal sensory afferents from the liver to the brainstem in colitis models reduced the colonic pTreg pool, resulting in increased susceptibility to colitis. These results demonstrate that the novel vago-vagal liver–brain–gut reflex arc tunes the number of pTreg cells and maintains the gut homeostasis. Intervening in this autonomic feedback feed-forward system could help develop new therapeutic strategies to treat or prevent immunological disorders of the gut.

DOI: 10.1038/s41586-020-2425-3

Source: https://www.nature.com/articles/s41586-020-2425-3

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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